Process of making CFTR modulators

Abstract

The disclosure provides processes for synthesizing Compound I, and pharmaceutically acceptable salts thereof. ##STR00001##

Claims

1. A method of preparing Compound I: ##STR00358## or a pharmaceutically acceptable salt thereof, comprising converting a compound of Formula (I): ##STR00359## or a salt thereof, into Compound I, or a pharmaceutically acceptable salt thereof, wherein: X.sup.a is selected from F, Cl, Br, I, and —OSO.sub.2R; R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro; and X.sup.c is selected from F, Cl, Br, and I.

2. The method of claim 1, wherein the conversion of the compound of Formula (I), or a salt thereof, into Compound I, or a pharmaceutically acceptable salt thereof, comprises the steps of: 1) combining the compound of Formula (I), or a salt thereof, with at least one first base to produce a compound of Formula (II): ##STR00360## or a salt thereof; and 2) combining the compound of Formula (II), or a salt thereof, with compound 1: ##STR00361## or a salt thereof, and at least one second base to produce Compound I, or a pharmaceutically acceptable salt thereof, wherein in the compound of Formula (II), or a salt thereof: X.sup.a is selected from F, Cl, Br, I, and —OSO.sub.2R; and R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro.

3. The method of claim 1, wherein the conversion of the compound of Formula (I), or a salt thereof, into Compound I, or a pharmaceutically acceptable salt thereof, comprises combining the compound of Formula (I), or a salt thereof, with compound 1: ##STR00362## or a salt thereof, and at least one third base to produce Compound I, or a pharmaceutically acceptable salt thereof, wherein in the compound of Formula (I), or a salt thereof: X.sup.a is selected from F, Cl, Br, I, and —OSO.sub.2R; R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro; and X.sup.c is selected from F, Cl, Br, and I.

4. The method of claim 1, wherein the compound of Formula (I): ##STR00363## or a salt thereof, is prepared by converting a compound of Formula (III): ##STR00364## or a salt thereof, into the compound of Formula (I), or a salt thereof, wherein in the compound of Formula (III), or a salt thereof: X.sup.a is selected from F, Cl, Br, I, and —OSO.sub.2R; R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro; X.sup.c is selected from F, Cl, Br, and I; and wherein: R.sup.1 is hydrogen and R.sup.2 is a monovalent nitrogen protecting group; R.sup.1 and R.sup.2 are independently selected from monovalent nitrogen protecting groups; or R.sup.1 and R.sup.2, together with the atoms to which they are attached, form a nitrogen protecting group.

5. The method of claim 4, wherein the compound of Formula (III): ##STR00365## or a salt thereof, is prepared by combining a compound of Formula (IV): ##STR00366## or a salt thereof, with a compound of Formula (V): ##STR00367## or a salt thereof, to produce the compound of Formula (III), or a salt thereof, wherein: X.sup.a is selected from F, Cl, Br, I, and —OSO.sub.2R; R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro X.sup.b is selected from Cl, F, —OC.sub.6F.sub.5, ##STR00368## X.sup.c is selected from F, Cl, Br, and I; and wherein: R.sup.1 is hydrogen and R.sup.2 is a monovalent nitrogen protecting group; R.sup.1 and R.sup.2 are independently selected from monovalent nitrogen protecting groups; or R.sup.1 and R.sup.2, together with the atoms to which they are attached, form a nitrogen protecting group.

6. The method of claim 5, wherein the compound of Formula (IV): ##STR00369## or a salt thereof, is prepared by converting a compound of Formula (VI): ##STR00370## or a salt thereof, into the compound of Formula (IV), or a salt thereof, wherein in the compound of Formula (VI), or a salt thereof: X.sup.a is selected from F, Cl, Br, I, and —OSO.sub.2R; and R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro.

7. The method of claim 6, wherein the compound of Formula (VI): ##STR00371## or a salt thereof, is prepared by combining compound 2: ##STR00372## or a salt thereof, with a compound of Formula (VII): ##STR00373## or a salt thereof, to produce the compound of Formula (VI), or a salt thereof, wherein in the compound of Formula (VII), or a salt thereof: X.sup.a is selected from F, Cl, Br, I, and —OSO.sub.2R; R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro; and X.sup.d is selected from F, Cl, Br, and I.

8. The method of claim 7, wherein compound 2: ##STR00374## or a salt thereof, is prepared by converting compound 3: ##STR00375## or a salt thereof, into compound 2, or a salt thereof.

9. The method of claim 8, wherein compound 3: ##STR00376## or a salt thereof, is prepared by converting compound 4: ##STR00377## or a salt thereof, into compound 3, or a salt thereof.

10. The method of claim 9, wherein compound 4: ##STR00378## or a salt thereof, is prepared by chiral resolution of compound (±)-4: ##STR00379## or a salt thereof.

11. A method of preparing Compound I: ##STR00380## or a pharmaceutically acceptable salt thereof, comprising converting a compound of Formula (VIII): ##STR00381## or a salt thereof, into Compound I, or a pharmaceutically acceptable salt thereof, wherein in the compound of Formula (VIII), or a salt thereof, X.sup.c is selected from F, Cl, Br, and I.

12. The method of claim 11, wherein the compound of Formula (VIII): ##STR00382## or a salt thereof, is prepared by converting a compound of Formula (IX): ##STR00383## or a salt thereof, into the compound of Formula (VIII), or a salt thereof, wherein in the compound of Formula (IX), or a salt thereof: X.sup.c is selected from F, Cl, Br, and I; and wherein: R.sup.1 is hydrogen and R.sup.2 is a monovalent nitrogen protecting group; R.sup.1 and R.sup.2 are independently selected from monovalent nitrogen protecting groups; or R.sup.1 and R.sup.2, together with the atoms to which they are attached, form a nitrogen protecting group.

13. The method of claim 12, wherein the compound of Formula (IX): ##STR00384## or a salt thereof, is prepared by combining a compound of Formula (X): ##STR00385## or a salt thereof, with a compound of Formula (V): ##STR00386## or a salt thereof, to produce the compound of Formula (IX), or a salt thereof, wherein in the compound of Formula (X), or a salt thereof: R.sup.1 is hydrogen and R.sup.2 is a monovalent nitrogen protecting group; R.sup.1 and R.sup.2 are independently selected from monovalent nitrogen protecting groups; or R.sup.1 and R.sup.2, together with the atoms to which they are attached, form a nitrogen protecting group; and wherein in the compound of Formula (V), or a salt thereof: X.sup.b is selected from Cl, F, —OC.sub.6F.sub.5, ##STR00387## and X.sup.c is selected from F, Cl, Br, and I.

14. The method of claim 13, wherein the compound of Formula (X): ##STR00388## or a salt thereof, is prepared by combining a compound of Formula (IV): ##STR00389## or a salt thereof, with compound 1: ##STR00390## or a salt thereof, to produce the compound of Formula (X), or a salt thereof, wherein in the compound of Formula (IV), or a salt thereof: X.sup.a is selected from F, Cl, Br, I, and —OSO.sub.2R; R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro; and wherein: R.sup.1 is hydrogen and R.sup.2 is a monovalent nitrogen protecting group; R.sup.1 and R.sup.2 are independently selected from monovalent nitrogen protecting groups; or R.sup.1 and R.sup.2, together with the atoms to which they are attached, form a nitrogen protecting group.

15. The method of claim 14, wherein the compound of Formula (IV): ##STR00391## or a salt thereof, is prepared by combining a compound of Formula (XI): ##STR00392## or a salt thereof, with a compound of Formula (VII): ##STR00393## or a salt thereof, to produce the compound of Formula (IV), or a salt thereof, wherein in the compound of Formula (XI), or a salt thereof: R.sup.1 is hydrogen and R.sup.2 is a monovalent nitrogen protecting group; R.sup.1 and R.sup.2 are independently selected from monovalent nitrogen protecting groups; or R.sup.1 and R.sup.2, together with the atoms to which they are attached, form a nitrogen protecting group; and wherein in the compound of Formula (VII), or a salt thereof: X.sup.a is selected from F, Cl, Br, I, and —OSO.sub.2R; R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro; and X.sup.d is selected from F, Cl, Br, and I.

16. The method of claim 15, wherein the compound of Formula (XI): ##STR00394## or a salt thereof, is prepared by converting a compound of Formula (XII): ##STR00395## or a salt thereof, into the compound of Formula (XI), or a salt thereof, wherein in the compound of Formula (XII), or a salt thereof, R.sup.3 is a monovalent nitrogen protecting group.

17. The method of claim 16, wherein the compound of Formula (XII): ##STR00396## or a salt thereof, is prepared by converting the compound of Formula (XV): ##STR00397## or a salt thereof, into the compound of Formula (XII), or a salt thereof, wherein in the compound of Formula (XV), or a salt thereof, R.sup.3 is a monovalent nitrogen protecting group.

18. The method of claim 17, wherein the conversion of the compound of Formula (XV), or a salt thereof, into the compound of Formula (XII), or a salt thereof, comprises the steps of: 1) Converting the compound of Formula (XV): ##STR00398## or a salt thereof, into the compound of Formula (XIV): ##STR00399## or a salt thereof; 2) Converting the compound of Formula (XIV), or a salt thereof, into the compound of Formula (XIII): ##STR00400## or a salt thereof; and 3) Converting the compound of Formula (XIII), or a salt thereof, into the compound of Formula (XII), or a salt thereof, wherein in the compounds of Formulae (XIII)-(XV), or a salt thereof, R.sup.3 is a monovalent nitrogen protecting group; and wherein in the compound of Formula (XIV), or a salt thereof: R.sup.4 is —SO.sub.2R; and R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro.

19. The method of claim 18, wherein the compound of Formula (XV): ##STR00401## or a salt thereof, is prepared by converting compound 2: ##STR00402## or a salt thereof, into the compound of Formula (XV), or a salt thereof.

20. The method of claim 19, wherein compound 2: ##STR00403## or a salt thereof, is prepared by converting compound 3: ##STR00404## or a salt thereof, into compound 2, or a salt thereof.

21. The method of claim 20, wherein compound 3: ##STR00405## or a salt thereof, is prepared by chiral resolution of compound (±)−3: ##STR00406## or a salt thereof.

22. The method of claim 21, wherein compound (±)−3: ##STR00407## or a salt thereof, is prepared by converting compound (±)−4: ##STR00408## or a salt thereof, into compound (±)−3, or a salt thereof.

23. The method of claim 22, wherein compound (±)−4: ##STR00409## or a salt thereof, is prepared by combining compound 5: ##STR00410## or a salt thereof, with 2-nitropropane to produce compound (±)−4, or a salt thereof.

24. The method of claim 2, wherein compound 1: ##STR00411## or a salt thereof, is prepared by converting compound 6: ##STR00412## or a salt thereof, into compound 1, or a salt thereof.

25. The method of claim 24, wherein compound 6: ##STR00413## or a salt thereof, is prepared by converting compound 7: ##STR00414## or a salt thereof, into compound 6, or a salt thereof.

26. The method of claim 25, wherein compound 7: ##STR00415## or a salt thereof, is prepared by combining compound 8: ##STR00416## or a salt thereof, with compound 9: ##STR00417## or a salt thereof, to produce compound 7, or a salt thereof.

27. The method of claim 26, wherein compound 8: ##STR00418## or a salt thereof, is prepared by converting compound 10: ##STR00419## or a salt thereof, into compound 8, or a salt thereof.

28. The method of claim 27, wherein compound 10: ##STR00420## or a salt thereof, is prepared by converting compound 11: ##STR00421## or a salt thereof, into compound 10, or a salt thereof.

29. The method of claim 28, wherein compound 11: ##STR00422## or a salt thereof, is prepared by converting compound 12: ##STR00423## or a salt thereof, into compound 11, or a salt thereof.

30. The method of claim 29, wherein compound 12: ##STR00424## or a salt thereof, is prepared by converting compound 13: ##STR00425## or a salt thereof, into compound 12, or a salt thereof.

31. The method of claim 30, wherein compound 13: ##STR00426## or a salt thereof, is prepared by converting compound 14: ##STR00427## or a salt thereof, into compound 13, or a salt thereof.

32. The method of claim 31, wherein compound 14: ##STR00428## or a salt thereof, is prepared by converting compound 15: ##STR00429## or a salt thereof, into compound 14, or a salt thereof.

33. The method of claim 32, wherein compound 15: ##STR00430## or a salt thereof, is prepared by converting compound 16: ##STR00431## or a salt thereof, into compound 15, or a salt thereof.

34. The method of claim 33, wherein compound 16: ##STR00432## or a salt thereof, is prepared by converting compound 17: ##STR00433## or a salt thereof, into compound 16, or a salt thereof.

35. The method of claim 34, wherein compound 17: ##STR00434## or a salt thereof, is prepared by converting compound 18: ##STR00435## or a salt thereof, into compound 17, or a salt thereof.

36. The method of claim 35, wherein compound 18: ##STR00436## or a salt thereof, is prepared by converting compound 19: ##STR00437## or a salt thereof, into compound 18, or a salt thereof.

37. A compound selected from: ##STR00438## ##STR00439## ##STR00440## and salts thereof, wherein: Xa is selected from F, Cl, Br, I, and —OSO.sub.2R; R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro; X.sup.b is selected from CI, F, —OC.sub.6F.sub.5, ##STR00441## X.sup.c is selected from F, Cl, Br, and I; X.sup.d is selected from F, Cl, Br, and I; R.sup.3 is a monovalent nitrogen protecting group; R.sup.4 is —SO.sub.2R; and R is selected from —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, and aryl optionally substituted with —C.sub.1-10alkyl, —C.sub.1-10haloalkyl, halo, or nitro; and wherein: R.sup.1 is hydrogen and R.sup.2 is a monovalent nitrogen protecting group; R.sup.1 and R.sup.2 are independently selected from monovalent nitrogen protecting groups; or R.sup.1 and R.sup.2, together with the atoms to which they are attached, form a nitrogen protecting group; and wherein the compound is not: ##STR00442## or a salt thereof.

Description

SYNTHETIC EXAMPLES

(1) Should the name of a compound conflict with the structure of the compound anywhere in the present application, the structure supersedes the name and is intended to be controlling.

Example 1: Synthesis of 3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylic acid (6)

(2) ##STR00237##

Step 1: Synthesis of [1,1′-bi(cyclopropan)]-1-ol (18)

(3) ##STR00238##

(4) A solution of methyl cyclopropanecarboxylate (109 g, 1.09 mol) in 2-MeTHF (1.31 L) and titanium(IV) isopropoxide (71 mL, 240.6 mmol) was stirred in a Morton flask then cooled to 18° C. Ethylmagnesium bromide (753 mL of 3 M, 2.259 mol) was added dropwise over 2 h to control the temperature between 15 to 20° C. The mixture was stirred for another 2 h then cooled to 5° C. and quenched drop-wise (slowly) with cold (˜5-10° C.) NaHSO.sub.4 (1.31 L of 20% w/v, 2.182 mol) while keeping the temperature below 10° C. The organic phase was isolated and the aqueous phase was re-extracted with hexanes (500 mL). The aqueous phase was discarded. The organic phases were combined, washed with sat. aq. NaHCO.sub.3(200 mL of 10% w/v, 238 mmol), dried over Na.sub.2SO.sub.4, and concentrated (30° C./˜40 torr) to afford 108.6 g of [1,1′-bi(cyclopropan)]-1-ol as a pale yellow liquid. The sample contained ˜8 wt % 2-MeTHF and 2 wt % iPrOH by .sup.1H NMR, so the corrected yield of the desired product was 91%.

(5) .sup.1H NMR (400 MHz, Chloroform-d) δ 1.99 (s, 1H), 1.35 (tt, J=8.2, 5.1 Hz, 1H), 1.22 (dd, J=9.0, 6.1 Hz, 1H), 0.70-0.65 (m, 2H), 0.52-0.45 (m, 2H), 0.43-0.38 (m, 2H), 0.21-0.15 (m, 2H).

Step 2: Synthesis of 1-bromo-1,1′-bi(cyclopropane) (17)

(6) ##STR00239##

(7) A solution of Ph.sub.3P (216 g, 824 mmol) in CH.sub.2Cl.sub.2 (770 mL) was cooled to −10° C. A solution of Br.sub.2 (132 g, 42.6 mL, 824 mmol) in CH.sub.2Cl.sub.2 (154 mL) was added over 15 min. The mixture was stirred for an additional 15 min then cooled further to −20° C. when pyridine (6.21 g, 6.35 mL, 78.5 mmol) was added. A solution of [1,1′-bi(cyclopropan)]-1-ol (77.0 g, 785 mmol), pyridine (65.2 g, 66.7 mL, 824 mmol), and DCM (385 mL) was added dropwise while maintaining the temperature at about −15 to −20° C. The mixture was stirred at −20 to −10° C. for 45 min then heated to reflux (42° C.) until the reaction was completed (˜1 h). The mixture was cooled to ambient temperature and concentrated to remove most of the solvent. The mixture was slurried in hexanes (1 L), allowed to stand overnight, then filtered. The filter-cake was washed with hexanes (2×500-mL). Then the combined filtrate and washings were washed with aq HCl (392 mL of 1 M, 392 mmol), then water (200 mL), then dried over Na.sub.2SO.sub.4, and concentrated to afford 82.2 g (65% yield) of 1-bromo-1,1′-bi(cyclopropane) as a yellow liquid.

(8) .sup.1H NMR (400 MHz, Chloroform-d) δ 5.30 (s, 1H), 1.61 (tt, J=8.2, 5.0 Hz, 1H), 1.07-1.02 (m, 2H), 0.78-0.66 (m, 2H), 0.67-0.51 (m, 2H), 0.35-0.21 (m, 2H).

Step 3: Synthesis of 1,1′-bi(cyclopropylidene) (16)

(9) ##STR00240##

(10) A solution of t-BuOK (62.7 g, 559 mmol) in DMSO (225 mL) was stirred at ambient temperature. Then a solution of crude 1-bromo-1-cyclopropyl-cyclopropane (75.0 g, 465.7 mmol) in DMSO (150 mL) was added dropwise while the temperature was maintained between 10 to 25° C. with an ice-water bath. After 1 h the addition was completed and the mixture was allowed to warm to ambient temperature. After 20 min .sup.1HNMR showed that the reaction was reasonably clean and nearly completed.

(11) After stirring overnight the product was isolated by flask-to-flask vacuum-distillation with the condenser at −5° C. and the receiver in an ice/i-PrOH bath. Vacuum was applied slowly from 100 to 40 torr. The pot external temperature was increased from 70 to 80° C. The distillate slowly collected (20-30° C. head temperature) in the receiver to afford 40.8 g of a colorless liquid that was a mixture of the desired product, t-BuOH and small amount of DMSO (1.0:1.1:0.15 molar ratio).

(12) The product above was re-distilled using a 14/20 6-inch Vigreaux column at atmospheric pressure under a nitrogen blanket. The condenser was cooled at 2° C. and the receiver was placed in an ice-water bath. The distillate collected (bp 60-62° C.) afforded 28.7 g as a colorless liquid which was again a mixture of desired product, t-BuOH, and DMSO (1.0:1.8:0.15 molar ratio). The calculated yield (.sup.1H NMR) was 10.0 g of 1,1′-bi(cyclopropylidene).

(13) The distillation was continued under reduced pressure (50-30 torr) while the external pot temperature was increased from ambient temperature to 70° C. Additional distillate was collected in a cooled receiver (ice/i-PrOH) to collect an additional 6.9 g of 1,1′-bi(cyclopropylidene) containing trace amounts of t-BuOH and DMSO, for a total yield of 16.9 g (45%).

(14) .sup.1H NMR (400 MHz, Chloroform-d) δ 1.19 (s, 8H).

Step 4: Synthesis of ethyl dispiro[2.0.2.SUP.4..1.SUP.3.]heptane-7-carboxylate (15)

(15) ##STR00241##

(16) A nitrogen-purged, 1-L jacketed reaction vessel was charged with Rh(OAc).sub.2 (14.43 g, 32.64 mmol), 1,1′-bi(cyclopropylidene) (170 g, 2.122 mol), and DCM (377.7 mL). The jacket was cooled at 0° C. (internal temperature 0.6° C.). A metering pump was used to add ethyl 2-diazoacetate (411.6 g, 379.4 mL, 3.607 mol) at 0.08 mL/min (4.8 mL/h). After 68 h (295 mL added), the addition was stopped (total ethyl 2-diazoacetate added was ˜320 mL or 1.3 equivalents). The dark amber reaction mixture was warmed to 20° C. Celite was added (29 g; 2 g/g catalyst) and the reaction mixture was allowed to stand overnight.

(17) A portion of the reaction mixture was filtered using a Celite-packed bed. A DCM-packed SiO.sub.2 (80 g) bed was prepared. The remaining unfiltered suspension was slurried with SiO.sub.2 (40 g) and filtered using the SiO.sub.2 bed under vacuum. The flask/bed were washed with DCM (3×400-mL). The Celite-filtrate and the SiO.sub.2 filtrate/washings were combined and concentrated to afford 409 g (116%) of a dark brown liquid.

(18) A bed of SiO.sub.2 (300 g) was packed with hexanes. The concentrated obtained above was dissolved in heptane/hexanes (˜300 mL). The resulting solution was loaded onto the packed SiO.sub.2 bed using hexanes (400 mL). The column was eluted with 10% EtOAc/hexanes, collecting ˜400-mL fractions—the eluting solvent turned orange (brown band stayed on the SiO.sub.2 bed): Fraction 1 orange; Fraction 2 yellow; Fraction 3 light yellow; Fraction 4 yellow-tinted. Fractions 1-3 were combined and concentrated to afford 341.6 g of ethyl dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylate (97% yield) as an orange liquid.

(19) .sup.1H NMR (400 MHz, Chloroform-d) δ 4.13 (q, J=7.2 Hz, 2H), 2.24 (s, 1H), 1.24 (t, J=7.1 Hz, 3H), 1.08-0.94 (m, 4H), 0.90-0.82 (m, 2H), 0.78 (ddd, J=8.3, 5.1, 3.6 Hz, 2H).

Step 5: Synthesis of dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-ylmethanol (13)

(20) ##STR00242##

(21) To a slurry of LiAlH.sub.4 (24 g, 616.0 mmol) in THF (750 mL) was slowly added a solution of ethyl dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylate (100 g, 601.6 mmol) in THF (250 mL) and the mixture came to a gentle reflux. The reaction temperature was controlled with an ice-bath and addition rate. The addition took 90 min and the mixture was stirred at ambient temperature for 16 hr. The mixture was chilled with an ice bath and the reaction was quenched with the addition of water (24 mL, 1.332 mol), followed by NaOH (24 mL of 2 M, 48.00 mmol), and then water (72 mL, 3.997 mol). The slurry was filtered over Celite and the filtrate was concentrated in vacuo. The oil was diluted with 300 mL of DCM and dried over MgSO.sub.4, filtered, and concentrated in vacuo affording dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylmethanol (58.5 g, 78%) as a light yellow oil.

(22) .sup.1H NMR (400 MHz, Chloroform-d) δ 3.71 (d, J=6.7 Hz, 2H), 1.71 (t, J=6.7 Hz, 1H), 1.51-1.39 (m, 1H), 0.93-0.81 (m, 4H), 0.71-0.61 (m, 2H), 0.61-0.49 (m, 2H).

Step 6: Synthesis of 7-(bromomethyl)dispiro[2.0.2.SUP.4..1.SUP.3.]heptane (12)

(23) ##STR00243##

(24) To a solution of Ph.sub.3P (98.5 g, 375.5 mmol) in DCM (600 mL) at −15° C. was added dropwise a solution of Br.sub.2 (59.6 g, 372.9 mmol) in DCM (100 mL). The reaction mixture was stirred at −15° C. for 15 min then chilled to −30° C. To the mixture was added dropwise a solution of dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylmethanol (43.2 g, 347.9 mmol) and pyridine (30 mL, 370.9 mmol) in DCM (100 mL) over 20 min. Following the addition, the reaction was stirred for 1 h at −5° C., at which time analysis by .sup.1H NMR showed complete reaction. The reaction mixture was concentrated in vacuo (35° C./200 torr) until approximately 100 mL of slurry remained. The slurry was diluted with ˜500 mL of 10% Et.sub.2O/hexane and the solid was filtered off. The filtrate was concentrated in vacuo affording more precipitate which was removed by filtration. The filtrate was concentrated again and the slurry was diluted with 250 mL 10% Et.sub.2O/hexanes. The precipitate was removed by filtration and washed with 50 mL of Et.sub.2O. The filtrate was concentrated in vacuo to afford 7-(bromomethyl)dispiro[2.0.2.sup.4.1.sup.3]heptane (65 g, 100%).

(25) .sup.1H NMR (400 MHz, Chloroform-d) δ 3.49 (d, J=7.5 Hz, 2H), 1.90 (t, J=7.5 Hz, 1H), 1.02-0.91 (m, 5H), 0.70 (ddd, J=9.2, 5.1, 4.0 Hz, 2H), 0.54 (dddd, J=8.6, 4.8, 3.7, 1.0 Hz, 2H).

(26) The product was used in the next step without further purification.

Step 7: Synthesis of 2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)acetonitrile (11)

(27) ##STR00244##

(28) To a solution of 7-(bromomethyl)dispiro[2.0.2.sup.4.1.sup.3]heptane (65 g, 347.5 mmol) in DMSO (400 mL) was added NaCN (17.5 g, 357.1 mmol). The red mixture was stirred at ambient temperature for 16 h. The reaction was poured into Na.sub.2CO.sub.3 (1,000 mL) and extracted three times with Et.sub.2O (500 mL). The combined organic phases were washed with water (500 mL), brine (500 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo affording 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)acetonitrile (45.9 g, 99%) as a dark red oil that contained residual Et.sub.2O and PPh.sub.3O.

(29) .sup.1H NMR (400 MHz, Chloroform-d) δ 2.42 (d, J=6.6 Hz, 2H), 1.69 (t, J=6.6 Hz, 1H), 1.03-0.88 (m, 4H), 0.78-0.68 (m, 2H), 0.64-0.55 (m, 2H).

Step 8: Synthesis of 2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)acetic acid (10)

(30) ##STR00245##

(31) To a solution of 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)acetonitrile (45 g, 337.9 mmol) in ethanol (300 mL) and water (100 mL) was added NaOH (100 g of 50% w/w, 1.250 mol). The mixture was stirred at 70° C. for 16 hr. The ethanol was removed in vacuo and the remaining aqueous phase was diluted with water (200 mL) and extracted two times with MTBE (400 mL). The aqueous phase was acidified with 6 M HCl (220 mL, 1.320 mol) and the dark mixture was extracted two times with MTBE (400 mL). The organic phase was washed with brine (400 mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo affording 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)acetic acid (31.8 g, 62%) as a dark yellow solid that contained MTBE and trace amount of PPh.sub.3O.

(32) .sup.1H NMR (400 MHz, Chloroform-d) δ 2.44 (d, J=6.9 Hz, 2H), 1.67 (t, J=6.9 Hz, 1H), 0.91 (ddd, J=9.0, 5.2, 3.9 Hz, 2H), 0.81 (dddd, J=8.9, 5.2, 4.0, 0.6 Hz, 2H), 0.68 (ddd, J=8.9, 5.2, 3.8 Hz, 2H), 0.55-0.45 (m, 2H).

Step 9: Synthesis of 2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethan-1-ol (8)

(33) ##STR00246##

(34) To a solution of 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)acetic acid (28.4 g, 186.6 mmol) in THF (320 mL) was added LiAlH.sub.4 (8.2 g, 210.5 mmol) (pellets). The mixture was stirred at ambient temperature for 16 h (.sup.1H NMR showed complete reaction). The reaction was quenched with the careful sequential addition of water (8.2 mL, 455.2 mmol), NaOH (8.2 mL of 15% w/w), then water (24.6 mL, 1.366 mol). To the slurry was added MgSO.sub.4, and the slurry was stirred at ambient temperature for 30 min. The light yellow precipitate was filtered off using Celite and washed with MTBE. The filtrate was concentrated in vacuo (35° C., 150 torr) affording 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethan-1-ol (24.3 g, 94% yield) as a yellow oil, which contained 9% MTBE.

(35) .sup.1H NMR (400 MHz, Chloroform-d) δ 3.62 (t, J=6.9 Hz, 2H), 1.68 (q, J=6.8 Hz, 2H), 1.39 (t, J=6.6 Hz, 1H), 0.89-0.74 (m, 4H), 0.65 (ddd, J=8.0, 4.7, 3.5 Hz, 2H), 0.53-0.44 (m, 2H).

Step 10: Synthesis of 1-(tert-butyl) 4-ethyl 3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (7)

(36) ##STR00247##

(37) DIAD (490 mL, 2.49 mol, 1.15 equiv) was added to a suspension of 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethan-1-ol (85 wt %, 345 g, 2.17 mol, 1 equiv), 1-tert-butyl 4-ethyl 3-hydroxy-1H-pyrazole-1,4-dicarboxylate (555.6 g, 2.17 mol, 1 equiv), and triphenylphosphine (654.6 g, 2.49 mol, 1.15 equiv) in toluene (3 L). After stirring at 40° C. overnight, the reaction was diluted with heptanes (1.2 L) and cooled to 20° C., over 60 min, allowing the bulk of the triphenylphosphine oxide-DIAD complex to crystallize out. Once at ambient temperature, the mixture was filtered, and the cake was washed with heptane (1.5 L) and suction dried. The filtrate was concentrated under reduced pressure to give crude 1-(tert-butyl) 4-ethyl 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate as a viscous yellow oil (1.2 kg). The residue was purified by flash column chromatography, eluting with 20% ethyl acetate in hexanes. The colorless oil was diluted with heptanes (200 mL) and stirred for ˜30 min at 0° C. The resulting white solid was filtered to give 1-(tert-butyl) 4-ethyl 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (603.7 g, 74% yield, >95% purity).

(38) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.31 (s, 1H), 4.37-4.26 (m, 4H), 1.92 (d, J=6.9 Hz, 2H), 1.64 (s, 9H), 1.36 (t, 1H), 1.32 (t, J=4.2 Hz, 3H), 0.86-0.82 (m, 4H), 0.64-0.60

(39) (m, 2H), 0.49-0.46 (m, 2H).

(40) Mass Spectrum (positive mode): m/z=377.3 [M+H].sup.+.

Step 11: Synthesis of 3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylic acid (6)

(41) ##STR00248##

(42) A 45% solution of potassium hydroxide in water (760 mL, 8.8 mol, 10.0 equiv) was added in portions maintaining the internal temperature at <50° C. to a heated solution (40° C.) of 1-(tert-butyl) 4-ethyl 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (330 g, 877 mmol, 1.0 equiv) in methanol (1 L). The reaction was stirred overnight at 50° C., at which point LCMS indicated the reaction was complete. The reaction was partially concentrated under reduced pressure to remove most of the methanol. The resulting solution was diluted with water (1.65 L) and 2-MeTHF (1 L). The layers were shaken vigorously and separated. The aqueous layer was washed again with 2-MeTHF (660 mL). The aqueous layer was cooled to 5° C. and adjusted to pH 1 with 6M aqueous HCl (2.24 L) portionwise, maintaining the internal temperature between 10 and 30° C. The product began to crystallize close to pH 7 and was accompanied with strong off-gassing. The resulting suspension was diluted with 2-MeTHF (2.7 L) and the product was allowed to dissolve into the organic layer. Stirring was stopped and the layers were separated. The aqueous layer was re-extracted with 2-MeTHF (660 mL). The combined organic layers were washed with saturated brine (660 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50° C. Heptanes (2 L) were added and the mixture was partially concentrated under reduced pressure to remove most of the 2-MeTHF. The mixture was stirred and cooled to room temperature. The resulting solid was filtered and washed with heptanes (660 mL). The product was dried under vacuum at 35° C. overnight to give 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylic acid (200.2 g, 92% yield, >99% purity) as a white solid.

(43) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.96 (s, 1H), 4.13 (t, J=13.0 Hz, 2H), 1.74 (t, J=6.9 Hz, 2H), 1.41 (t, 1H), 0.83-0.77 (m, 4H), 0.62-0.57 (m, 2H), 0.45-0.41 (m, 2H).

(44) Mass Spectrum (positive mode): m/z=497.2 [2M+H].sup.+.

Example 2: Alternative Synthesis of 3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-H-pyrazole-4-carboxylic acid (6)

(45) ##STR00249##

Step 1: Synthesis of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (24)

(46) ##STR00250##

(47) 55% w/w hydrazine hydrate (29 mL, 515 mmol, 1.03 equiv) was added dropwise to a solution of diethyl 2-(ethoxymethylene)propanedioate (108 g, 500 mmol, 1 equiv) in ethanol (0.45 L). The resulting mixture was heated to reflux for 20 h, after which HPLC indicated complete reaction. The mixture was a slurry upon cooling to ambient temperature. The solid was collected by filtration, washed with EtOH (2×100 mL), and dried in a vacuum oven at 40° C. to afford 46 g (60%) of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate as an off-white solid.

Step 2: Synthesis of ethyl 3-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (23)

(48) ##STR00251##

(49) 2,3-Dihydropyran (18 mL, 197.2 mmol, 1.03 equiv) was added to a solution of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (30 g, 192 mmol, 1 equiv) in acetonitrile (180 mL) and the resulting mixture was cooled at 0° C. p-Toluenesulfonic acid hydrate (1.26 g, 6.6 mmol, 0.035 equiv) was added as a solid in one portion. After 2 h the mixture was allowed to warm to 10° C. After 2 h, HPLC indicated complete conversion. The solid was collected by filtration, washed with acetonitrile (2×35 mL), and dried in a vacuum oven at 40° C. to give ethyl 3-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (39.2 g, 85%) as an off-white solid.

Step 3: Synthesis of ethyl 3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (21)

(50) ##STR00252##

(51) A mixture of 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethyl methanesulfonate (9.2 g, 43.2 mmol, 1.04 equiv) and ethyl 3-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (10 g, 41.6 mmol, 1 equiv) in DMF (50 mL) was stirred at room temperature. Then 1,1,3,3-tetramethylguanidine (5.7 mL, 45.7 mmol, 1.1 equiv) was added, and the mixture was heated at 60° C. After heating for 12 h, HPLC showed complete reaction. 100 mL of water was added followed by 75 mL of ethyl acetate. The phases were separated, and the organic layer was washed with 25 ml of water. The organic layer was filtered, concentrated, and dried in a vacuum oven at 40° C. to give ethyl 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (14.3 g) as a light yellow solid, which was used without further purification.

Step 4: Synthesis of ethyl 3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate (20)

(52) ##STR00253##

(53) A solution of ethyl 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (7.15 g, 19.7 mmol, 1 equiv) in 4N HCl in 1,4-dioxane (138 mL, 572 mmol, 29 equiv) was stirred at room temperature. A precipitate started forming after about 30 min stirring. After 1 h, heptane (75 mL) was added and the solid was collected by filtration, washed with heptane (2×10 mL), and dried in a vacuum oven at 40° C. to afford ethyl 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate (4.03 g) as a light yellow solid, which was used subsequently.

Step 5: Synthesis of 3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylic acid (6)

(54) ##STR00254##

(55) 45% Aqueous potassium hydroxide solution (6 g, 106 mmol, 10 equiv) was added to a solution of ethyl 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate (4.03 g, 14.5 mmol, 1.0 equiv) in methanol (12 mL) and the mixture was stirred at 45° C. for 20 h. Water (20 mL) and 2-methyltetrahydrofuran (18 mL) were added and the layers were separated. The water layer was washed with 2-methyltetrahydrofuran (8 mL) and adjusted to pH 1 with 6 N HCl. 2-Methyltetrahydrofuran (35 mL) was added and the layers were separated. The water phase was washed with 2-methyltetrahydrofuran (20 mL). The organic layers were combined and washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylic acid as a white solid (2.73 g, 95.3% purity, 48% yield over 3 steps from 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethyl methanesulfonate).

Example 3: Alternative Synthesis of dispiro[2.0.2.SUP.4..1.SUP.3.]heptane-7-carboxylic acid (14)

(56) ##STR00255##

Step 1: Synthesis of ethyl 2-cyclopropylideneacetate (26)

(57) ##STR00256##

(58) (1-Ethoxycyclopropoxy)trimethylsilane (200 g, 1147 mmol, 1.1 equiv) was added to a 3000 mL round-bottomed flask equipped with a magnetic stir bar. Then methanol (600 mL) was added and the resulting solution was stirred overnight at room temperature. The solvent was evaporated under reduced pressure (water bath at 25° C.). The oil that remained was dissolved in tetraethylene glycol dimethyl ether (700 mL) with a magnetic stir bar. Then benzoic acid (28 g, 229 mmol, 0.22 equiv) was added and the resulting mixture was heated to 100° C. (heat block). Ethyl (triphenylphosphoranylidene) acetate (360 g, 1033 mmol, 1.0 equiv) was dissolved in dichloromethane (550 mL) in a 1000 mL addition funnel and added dropwise to the above solution of cyclopropanone over a 2 h time period. After the addition, the switch of addition funnel was closed to collect condensed dichloromethane. The resulting mixture was heated at 100° C. for another h and then cooled to room temperature. Then the reaction mixture was purified by fractional distillation at 0.54 Torr between 83-100° C. (cooling temperature of fluid in condenser was at −6° C., all distillate under this condition was identified as the product) to give a total of crude ethyl 2-cyclopropylideneacetate (164.19 g, 61% purity by Q-NMR). The crude ethyl 2-cyclopropylideneacetate was dissolved in pentane (400 mL), washed with ice cold saturated sodium carbonate solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure (water bath at 25° C.) to give ethyl 2-cyclopropylideneacetate (92.52 g, 80% purity by Q-NMR, 57% yield) as a colorless liquid

(59) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.23 (t, J=1.8 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 1.49-1.42 (m, 2H), 1.33-1.20 (m, 5H).

(60) Mass Spectrum (positive mode): m/z=125.8 [M].sup.+.

Step 2: Synthesis of ethyl dispiro[2.0.2.SUP.4..1.SUP.3.]heptane-7-carboxylate (15)

(61) ##STR00257##

(62) Cyclopropyl(diphenyl)sulfonium (tetrafluoroborate) (95%, 265 g, 800 mmol, 1.01 equiv) was dissolved in non-anhydrous dimethyl sulfoxide (4000 mL) in a 22 L round-bottomed flask equipped with an overhead stirrer. Room temperature water was added to the secondary container. Ethyl 2-cyclopropylideneacetate (79% purity by Q-NMR, 33.75 g; 80% purity by Q-NMR, 92.52 g, 793 mmol, 1.0 equiv) was added, followed by cesium hydroxide hydrate (containing about 10% H.sub.2O, 133 g, 800 mmol, 1.01 equiv) in one portion. At 120 min, ice was added to the secondary container and the reaction was diluted with ice cold methyl tert-butyl ether (8 L). Ice cold saturated ammonium chloride solution (6 L) was added slowly while keeping the temperature below 25° C. The aqueous layer was extracted with methyl tert-butyl ether (4 L×3), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure (water bath at 25° C.) to give a total of crude ethyl dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylate (316.67 g) as a pale yellow liquid.

(63) Crude ethyl dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylate with 17% ethyl 2-cyclopropylideneacetate (68.17 g, ˜170.7 mmol, 1.0 equiv) was dissolved in non-anhydrous dimethyl sulfoxide (300 mL) at room temperature. Cyclopropyl(diphenyl)sulfonium (tetrafluoroborate) (95%, 19.2 g, 58 mmol, 0.34 equiv) was added, followed by cesium hydroxide hydrate (containing about 10% H.sub.2O, 9.7 g, 58 mmol, 0.34 equiv) in one portion. At 120 min, the reaction was diluted with methyl tert-butyl ether (800 mL). The DMSO layer was separated and cooled to 0° C. with an ice bath. The MTBE layer was washed with saturated ammonium chloride solution (650 mL). This aqueous layer was separated and slowly added to the above DMSO mixture. The resulting aqueous layer was extracted with methyl tert-butyl ether (800 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure (water bath at 25° C.) to give crude ethyl dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylate. (Another batch (204.51 g of crude ethyl dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylate with 17% ethyl 2-cyclopropylideneacetate used) of this reaction was processed in same manner, and both batches were combined for purification. Then this combined mixture was purified by fractional distillation at 0.68 Torr between 68-120° C. (cooling temperature of fluid in condenser was at −6° C., all distillate under this condition was identified as the product) to give crude ethyl dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylate (83.32 g, 65% purity by Q-NMR, 47% yield) as a colorless liquid.

(64) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 6.23 (t, J=1.8 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 1.49-1.42 (m, 2H), 1.33-1.20 (m, 5H).

(65) Mass Spectrum (positive mode): m/z=165.1 [M−H].sup.+.

Step 3: Synthesis of dispiro[2.0.2.SUP.4..1.SUP.3.]heptane-7-carboxylic acid (14)

(66) ##STR00258##

(67) To a crude mixture of ethyl dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylate (5.0 g, 30.0 mmol, 1.0 equiv) and diphenyl sulfide (6.24 g) in methanol/THF (8:1, 126 mL) was added lithium hydroxide (0.72 g, 30.0 mmol, 1.0 equiv) and a solution of sodium hydroxide (21.0 g, 525.0 mmol, 17.5 equiv) in water (30 mL). The resulting mixture was stirred at 40° C. overnight. The solvents were removed under reduced pressure, then the residue was dissolved in water (80 mL) and washed with methyl tert-butyl ether (80 mL). The pH of the aqueous layer was adjusted to 2 using 5N HCl (˜110 mL). The precipitate was collected by suction filtration and dried to constant weight to give dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylic acid (2.98 g, 72% yield, >95% purity) as a white solid.

(68) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.26 (s, 1H), 1.11-1.02 (m, 4H), 0.90-0.80 (m, 4H).

(69) Mass Spectrum (positive mode): m/z=137.0 [M−H].sup.+.

Example 4: Alternative Synthesis of 2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)acetic acid (10)

(70) ##STR00259##

Step 1: Synthesis of dispiro[2.0.2.SUP.4..1.SUP.3.]heptane-7-carboxylic acid (14)

(71) ##STR00260##

(72) Sodium hydroxide (21.5 g, 542 mmol, 2.0 equiv) was added to a solution of ethyl dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylate (45.0 g, 271 mmol, 1 equiv) in a 4:1 mixture of methanol and water (500 mL) and stirred at 55° C. for 4 h. LC-MS indicated the reaction was complete. Most of solvents were removed under reduced pressure, then the residue was suspended in water (100 mL) and the pH was adjusted to 2 using 5N HCl. The precipitate that formed was collected by suction filtration and dried to constant weight to give dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylic acid (31 g, 85% yield, >95% purity) as an off-white solid.

(73) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.25 (s, 1H), 1.05 (m, 4H), 0.88-0.96 (m, 4H).

(74) Mass Spectrum (positive mode): m/z=136.9 [M−H].sup.+.

Step 2: Synthesis of 2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)acetic acid (10)

(75) ##STR00261##

(76) Thionyl chloride (176 mL, 2.4 mol, 9.6 equiv) was added to dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylic acid (35 g, 251 mmol, 1.0 equiv), and the resulting solution was heated at 60° C. for two h. The reaction was cooled to room temperature and concentrated under reduced pressure, and then azeotroped with toluene (2×50 mL) until all the thionyl chloride was removed. The residue was diluted with anhydrous acetonitrile (3 L). Trimethylsilyl diazomethane (2M in hexanes, 190 mL, 380 mmol, 1.5 equiv) was added over 5 min. After stirring for 2 h, silver acetate (64 g, 380 mmol, 1.5 equiv), triethylamine (70 mL, 502 mmol, 2.0 equiv) and water (200 mL) were sequentially added. After stirring overnight, the reaction was filtered through a 2 inch pad of Celite, which was rinsed with acetonitrile (100 mL). The combined filtrates were concentrated under reduced pressure to remove most of the acetonitrile. The resulting semi solid was diluted with 1N HCl (300 mL) and dichloromethane (300 mL). The mixture was filtered again through Celite (1 inch pad), which was washed with additional dichloromethane (100 mL). The layers were separated and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)acetic acid (28 g, 78% yield, 85% purity by GC-MS) as a yellow solid (containing ˜2.3% of dispiro[2.0.2.sup.4.1.sup.3]heptane-7-carboxylic acid).

(77) .sup.1H NMR (400 MHz, Chloroform-d) δ 2.44 (d, J=6.9 Hz, 2H), 1.67 (t, J=6.9 Hz, 1H), 0.91 (ddd, J=9.0, 5.2, 3.9 Hz, 2H), 0.81 (dddd, J=8.9, 5.2, 4.0, 0.6 Hz, 2H), 0.68 (ddd, J=8.9, 5.2, 3.8 Hz, 2H), 0.55-0.45 (m, 2H).

Example 5: Alternative Synthesis of 2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)acetic acid (10)

(78) ##STR00262##

Step 1: Synthesis of ethyl 2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)-2-oxoacetate (28)

(79) ##STR00263##

(80) A solution of ethyl 3-diazo-2-oxopropionate (16.2 g, 125 mmol, 2.0 equiv) in dichloromethane (˜48 mL; total volume of solution was 60 mL) was added to a suspension of rhodium octanoate dimer (0.78 g, 1 mmol, 0.016 equiv) and 1,1′-bi(cyclopropylidene) (5 g, 62.5 mmol, 1 equiv) in dichloromethane (10 mL) at 0° C. by a syringe pump at 0.04 mL/min over 24 h, keeping the needle tip under the solvent surface. After 24 h, .sup.1H-NMR analysis showed 80% conversion of starting material (including ˜10% of homo-coupling by-products). The reaction mixture was allowed to warm up to room temperature, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography, eluting with a gradient of 0 to 30% ethyl acetate in heptanes (RediSep 2×220 g) to give ethyl 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)-2-oxoacetate (7.1 g, 58% yield, >95% purity by .sup.1HNMR) as a light-yellow liquid.

(81) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 4.28 (q, J=7.2 Hz, 2H), 3.24 (s, 1H), 1.35 (t, J=7.2 Hz, 3H), 1.15-1.09 (m, 2H), 1.01-0.95 (m, 2H), 0.92-0.80 (m, 4H).

(82) Mass spectrum (positive mode): m/z=195.1 [M+H].sup.+.

Step 2: Synthesis of 2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)acetic acid (10)

(83) ##STR00264##

(84) Ethyl 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)-2-oxoacetate (5 g, 25.7 mmol, 1.0 equiv) was added dropwise to a solution of hydrazine hydrate (50-60% in water, 4.95 g, 77 mmol, 3.0 equiv) and water (5 mL) at −20° C. The reaction mixture became a loose solid after addition. The mixture was warmed to room temperature over 30 min and heated to 80° C. for 5 min. After the reaction mixture was cooled to room temperature, potassium hydroxide (3.6 g, 64.4 mmol, 2.5 equiv) was added in three portions while the reaction mixture became a solution. The reaction was stirred at 80° C. for 16 h, after which GC-MS indicated the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (15 mL), and washed with diethyl ether (30 mL). The aqueous layer was adjusted to pH 1 with concentrated HCl (˜6 mL). The aqueous layer was extracted with toluene (4×50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)acetic acid (3.2 g, 82% yield, 94% purity by .sup.1HNMR and GC-MS) as a light yellow solid.

(85) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.44 (d, J=6.9 Hz, 1H), 1.63 (t, 1H), 0.91-0.88 (m, 2H), 0.82-0.80 (m, 2H), 0.68 (m, 2H), 0.52 (m, 2H).

(86) Mass Spectrum (positive mode): m/z=151.1 [M−H].sup.+.

Example 6: Alternative Synthesis of 1-(tert-butyl) 4-ethyl 3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (7)

(87) ##STR00265##

Step 1: Synthesis of 2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethyl methanesulfonate (22)

(88) ##STR00266##

(89) A mixture of 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)-ethan-1-ol (20 g, 144.6 mmol, 1 equiv) and triethylamine (26.1 mL, 185.8 mmol; 1.28 equiv) in 2-MeTHF (160 mL) was cooled at 0° C. A solution of MsCl (15.1 mL, 193.7 mmol; 1.34 equiv) in 2-MeTHF (90 mL) was added dropwise over 1 h while maintaining the reaction temperature at 0° C. After the addition was completed, the mixture was stirred at 0° C. for an additional 1 h. The mixture was allowed to warm to ambient temperature. The reaction mixture was quenched with water (80 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCO.sub.3(80 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was vacuum-dried to afford 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethyl methanesulfonate (33.1 g) as a brown solid, which was used subsequently.

Step 2: Synthesis of 1-(tert-butyl) 4-ethyl 3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (7)

(90) ##STR00267##

(91) A mixture of 1-tert-butyl 4-ethyl 3-hydroxy-1H-pyrazole-1,4-dicarboxylate (38.7 g, 151.2 mmol, 1 equiv), 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethyl methanesulfonate (33.1 g, 152.7 mmol; 1.01 equiv), and Cs.sub.2CO.sub.3 (55.1 g, 169.3 mmol; 1.12 equiv) in DMF (180 mL) was heated at 50° C. for 24 h. After cooling to room temperature, the reaction mixture was diluted with water (360 mL) and 2-MeTHF (360 mL), and the phases were separated. The aqueous phase was extracted with 2-MeTHF (2×150 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography system, eluting with a gradient of 0 to 35% ethyl acetate in heptanes (RediSep 220 g) to give compound 1-(tert-butyl) 4-ethyl 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (34.3 g, 67% yield over 2 steps from 2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)-ethan-1-ol, 97% purity) as a white solid.

(92) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.32 (s, 1H), 4.35 (t, J=8.0 Hz, 2H), 4.31 (q, J=8.0 Hz, 2H), 1.93 (q, J=8.0 Hz, 2H), 1.63 (s, 9H), 1.48 (t, J=6.4 Hz, 1H), 1.35 (t, J=8.0 Hz, 3H), 0.90-0.78 (m, 4H), 0.67-0.62 (m, 2H), 0.50-0.47 (m, 2H).

(93) Mass spectrum (positive mode): m/z=377.2 [M+H].sup.+.

Example 7: Synthesis of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (49)

(94) ##STR00268##

Step 1: Preparation of (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one (4)

(95) ##STR00269##

(96) Racemic 3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one was dissolved in 80 g/L+/−8 g/L in MeOH/ACN 70/30 v/v (target 80+/−2 g/L) and separated on Chiralpak AD 20 μm as the stationary phase using MeOH/ACN 70/30 v/v as the mobile phase. (S)-3-(2-Methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one is Peak 2. Optional recrystallization of (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one: (S)-3-(2-Methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one (9.5 kg, 1.0 equiv) was stirred in isopropanol (76 L, 8 vol) then heated to >70° C. to dissolve the solid. The mixture was then cooled to 20° C. over 4-5 h, the solid isolated by filtration, and the cake washed with isopropanol (4.75 L, 0.5 vol) and pulled dry. The material was dried under vacuum to afford (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one in 90% recovery.

Step 2: Synthesis of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3)

(97) ##STR00270##

(98) A suspension of Raney Nickel 2400 (77 wt %, 2.8 kg) was allowed to settle for 2 days. The standing liquid was decanted to waste and the remaining catalyst was charged to a reactor with the aide of water (2.6 kg), then degassed with N.sub.2. In a second reactor, a mixture of (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one (13.9 kg) and EtOH (170.8 kg) was heated to 30° C., then degassed with N.sub.2, then transferred to the reactor containing Raney Nickel. The transfer was completed with the aid of an EtOH (29.8 kg) rinse. The mixture was purged three times with nitrogen and purged three times with hydrogen. The contents of the reactor were heated to 60-65° C. and stirred under H.sub.2 (4-8 psi) until the reaction was completed (18 h). The mixture was cooled to 15-20° C., then purged with nitrogen three times, then filtered through a pad of Celite (3.0 kg) wetted with EtOH (3.2 kg). The reactor and Celite cake were washed with EtOH (2×14.0 kg). The filtrate was distilled to a final volume of approx. 25 L then heated to 45° C. MTBE (269.4 kg) was then charged maintaining a temperature of 48-50° C. and then distilled at ambient pressure at 48-55° C. to a final volume of approx. 30 L. Two further portions of MTBE (269.4 kg then 187.4 kg) were sequentially added then concentrated to approx. 30 L volume.

(99) The contents of the reactor were seeded with (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (70.1 g) at 40° C. The seeded crystal slurry was cooled to 15° C. over a period of 3.5 h, then stirred for 16.5 h between 12-15° C. then filtered. The reactor and filter cake were then washed with cold (−2 to −10° C.) MTBE (2×10 kg). The filter-cake was dried to a constant weight which afforded (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (10.4 kg; 88%) as a white, crystalline solid.

(100) Recrystallization of (S)-3-(3-Hydroxypropyl)-5,5-dimethylpyrrolidin-2-one: A mixture of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (10.3 kg) and DCM (28.2 kg) was stirred and heated to 25° C. for 2 h then transferred to another reactor through an in-line filter (45 um). The initial reactor was rinsed with DCM (6.8 kg) at 21° C. for 10 min then transferred to the reactor through the in-line filter. MTBE (38.1 kg) was charged to the solution at 25-30° C. then the mixture was distilled over a period of 2.5 h at 35-52° C. at atmospheric pressure to a final volume of approx. 30 L. MTBE (38.2 kg) was charged to the reactor at 45-50° C. The resulting suspension was distilled over a period of 3.25 h at 49-55° C. at atmospheric pressure to a final volume of approx. 30 L. The contents of the reactor were cooled to 21° C. over a period of 2.5 h and stirred for 16 h at 20° C. The suspension was filtered. The reactor and filter cake were rinsed with MTBE (7.7 kg, 0.0° C.). The filter cake was dried over a period of 2 days. Yield: 9.1 kg (88.3%) of an off-white solid.

(101) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.63 (s, 1H), 4.38 (s, 1H), 3.38 (t, J=6.5 Hz, 2H), 2.37 (qd, J=9.5, 4.4 Hz, 1H), 2.02 (dd, J=12.4, 8.6 Hz, 1H), 1.78-1.63 (m, 1H), 1.50-1.33 (m, 3H), 1.16 (d, J=17.9 Hz, 7H).

(102) ESI-MS m/z calc. 171.12593, found 172.0 [M+1]+.

(103) GCMS:100% (AUC).

(104) Chiral HPLC: 100% (AUC).

Step 3: Synthesis of (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (2)

(105) ##STR00271##

(106) LiAlH.sub.4 pellets (332.5 g, 8.760 mol, 1.50 equiv) were slowly added to a reactor with 2-MeTHF (10.00 L, 10 vol) at 30-40° C. The mixture was then heated to 75° C. A mixture of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (1,000 g, 5.840 mol, 1.00 equiv) and 2-MeTHF (10.00 L, 10 vol) was prepared in a separate reactor and heated to 65° C., which was then carefully transferred to the reactor containing the LiAH.sub.4 mixture over 2 h. The mixture was stirred at 70° C. until the reaction was complete (18-24 h) then cooled to 0-10° C. Water (400.0 mL, 1×LiAlH.sub.4 wt) was then carefully added while maintaining the mixture temperature at <30° C. A solution of aq 15% NaOH (400.0 mL, 1×LiAlH.sub.4 wt) was then added followed by water (400.0 mL, 1×LiAlH.sub.4 wt) while maintaining the mixture temperature at <30° C. The resulting mixture was then heated to 60° C. and held at that temperature for at least 30 min. The mixture was cooled to 20-30° C. then Celite (200 grams, 20 wt %) was added. The mixture was then filtered through a pad of Celite. The reactor and filter cake were rinsed with 2-MeTHF (4.0 L, 4.0 vol). The filtrate was concentrated under vacuum to afford pyrrolidine compound (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (872 g; 94.95% yield) as a clear oil.

(107) .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) δ 3.36 (t, J=6.3 Hz, 3H), 2.95 (dd, J=10.6, 7.6 Hz, 1H), 2.40 (dd, J=10.6, 7.7 Hz, 1H), 2.12-1.97 (m, 1H), 1.69 (dd, J=12.1, 8.2 Hz, 1H), 1.47-1.25 (m, 5H), 1.08 (s, 3H), 1.02 (s, 3H).

Step 4: Synthesis of (S)-6-bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide

(108) ##STR00272##

(109) A mixture of (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (2325 g, 14.8 mol) and 6-bromo-2-fluoropyridine-3-carboxamide (3400 g, 15.5 mol) in 2-methyltetrahydrofuran (23 L) was stirred, then potassium carbonate (2650 g, 19.2 mol) and deionized water (7 L) were added. The mixture was stirred at <25° C. until the reaction was complete (≥16 h).

(110) The aqueous phase was removed and the upper organic phase was washed with water (7 L) and 2% aqueous sodium chloride (7 L). The organic layer was concentrated under reduced pressure to about 19 L. 2-Methyltetrahydrofuran was chased from the mixture by two sequential additions and concentrations of acetonitrile (2×20 L) followed by distillation. To the remaining solution was added acetonitrile (20 L) and the reaction was warmed to 85° C. for 2 h and then cooled at 10° C./h to 25° C. The slurry was cooled to 10° C. and stirred for 4 h then filtered. The cake was rinsed two times with acetonitrile (2×3 L) then the solid was dried under vacuum to afford (S)-6-bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide as a crystalline white solid (3850 g, 73% yield).

(111) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.78 (s, 1H), 7.39 (s, 1H), 7.34 (dd, J=7.7, 1.0 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 4.42 (t, J=5.1 Hz, 1H), 3.39 (q, J=5.7 Hz, 2H), 3.29-3.12 (m, 2H), 2.19 (dt, J=10.9, 5.8 Hz, 1H), 1.92 (dd, J=11.9, 5.7 Hz, 1H), 1.53 (s, 3H), 1.50 (s, 3H), 1.48-1.29 (m, 5H).

Step 5: Synthesis of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (49)

(112) ##STR00273##

(113) A mixture of (S)-6-bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (2.65 kg, 7.4 mol), 2-methyltetrahydrofuran (16 L), and triethylamine (900 g, 8.88 mol) was stirred at 20° C., then methanesulfonyl chloride (933 g, 8.14 mol) was added over 2 h. The mixture was stirred at 20° C. until the reaction was completed (typically 16 h). The resulting mixture was filtered and the filter cake was rinsed with tert-butyl methyl ether (2×4 L). The combined filtrates (containing the mesylate intermediate) were transferred to a reactor and diluted with dimethyl sulfoxide (16 L). To the mixture was added phthalimide (1198 g, 8.14 mol). The mixture was stirred until a solution was obtained, then potassium carbonate (1023 g, 7.4 mol) was added and the mixture was stirred and heated to 70° C. until the reaction was completed (2 h). The mixture was cooled to 20° C. and diluted with 2-methyltetrahydrofuran (16 L), followed by the addition of deionized water (21 L). The phases were separated and the upper organic phase was washed with deionized water (10 L) and saturated aqueous sodium chloride (2×1 L). The organic phase was diluted with toluene (16 L) and concentrated under reduced pressure to approximately 10 L volume. The solid was isolated by filtration and the filter cake was rinsed with toluene (2×2 L). The resulting solid was dried to afford compound (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide as an off-white solid (3393 g, 6.99 mol, 94% yield).

(114) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.91-7.80 (m, 4H), 7.80-7.71 (m, 1H), 7.42-7.36 (m, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.29-7.09 (m, 3H), 6.67 (d, J=7.7 Hz, 1H), 3.59 (t, J=6.9 Hz, 2H), 3.23 (t, J=10.4 Hz, 1H), 3.16 (dd, J=10.2, 7.4 Hz, 1H), 2.30 (s, 2H), 2.28-2.13 (m, 1H), 1.90 (dd, J=12.0, 5.6 Hz, 1H), 1.71-1.53 (m, 2H), 1.51 (s, 3H), 1.48 (s, 3H), 1.47-1.23 (m, 3H).

Example 8: Synthesis of (R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide

(115) The reactions in this example provide (R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide, because (S)-(−)-α-methylbenzylamine was used as a reagent. (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide can be obtained using the same reactions and (R)-(−)-α-methylbenzylamine as a reagent.

(116) ##STR00274## ##STR00275##

Step 1: Synthesis of tert-butyl (3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propyl)carbamate (37)

(117) ##STR00276##

(118) To a stirring solution of 3-tert-butoxycarbonylamino-propionic acid (30.0 g, 158.6 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (27.4 g, 190.3 mmol) and 4-dimethylaminopyridine (31.03 g, 254.0 mmol) in dichloromethane (600 mL) at 0° C. was dropwise added a solution of N,N-dicyclohexylcarbodiimide (39.3 g, 190.3 mmol) in dichloromethane (300 mL). After the addition was complete, the reaction mixture was allowed to warm up to room temperature and stirred for 16 h. The precipitated dicyclohexylurea was filtered off, and the filtrate was washed with 5% aqueous potassium bisulfate solution (3×200 mL) followed by brine (100 mL) and dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was cooled to 0° C. Glacial acetic acid (91 mL, 1.59 mol) was slowly added, followed by a portionwise addition of sodium borohydride (15.0 g, 397.0 mmol). After the addition was complete, the reaction mixture was allowed to warm up to room temperature and stirred for 18 h. The reaction mixture was re-cooled to 0° C. and quenched with water (200 mL). The organic layer was separated, washed with water (2×300 mL) followed by brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to afford crude 2,2-dimethyl-5-(3-tert-butoxycarbonylamino-propyl)-[1,3]dioxane-4,6-dione (49.05 g, 103%, contained ˜10% of unreacted 2,2-dimethyl-[1,3]dioxane-4,6-dione) as an off-white solid. The crude product was carried to the next step without further purification.

(119) LCMS Method: Final purity was determined by reverse phase HPLC using a Kinetex C18 column (50×3.0 mm) and a dual gradient run from 5-100% mobile phase B over 12 min. Mobile phase A=water (0.1% CF.sub.3CO.sub.2H). Mobile phase B=acetonitrile (0.1% CF.sub.3CO.sub.2H). Flow rate=1.5 mL/min, injection volume=10 μL, and column temperature=30° C.

(120) .sup.1H NMR (250 MHz, CDCl.sub.3) δ (ppm): 4.62 (broad s, 1H), 3.74-3.72 (m, 1H), 3.22-3.15 (m, 2H), 2.17-2.08 (m, 2H), 1.81 (s, 3H), 1.75 (s, 3H), 1.70-1.66 (m, 2H), 1.43 (s, 9H).

(121) ESI-MS m/z calc. 301.3, found 302.2 [M+1]+. Retention time: 3.87 min.

Step 2: Synthesis of ethyl 5-((tert-butoxycarbonyl)amino)-2-methylenepentanoate (36)

(122) ##STR00277##

(123) To a stirring solution of 2,2-dimethyl-5-(3-tert-butoxycarbonylamino-propyl)-[1,3]dioxane-4,6-dione (23.7 g, 78.6 mmol) in anhydrous ethanol (850 mL) under nitrogen atmosphere was added N,N′-dimethylmethyleneiminium iodide (36.5 g, 197.0 mmol). The reaction mixture was heated to 65° C. for 18 h. The reaction mixture was concentrated and the crude product was extracted with ethyl acetate (400 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (400 mL), 10% aqueous potassium bisulfate (400 mL), and brine (100 mL), then dried over anhydrous sodium sulfate and concentrated. The product was purified by silica gel column chromatography using 0-15% hexanes-ethyl acetate to afford 5-tert-butoxycarbonylamino-2-methylene-pentanoic acid ethyl ester (14.76 g, 73%) as a colorless oil.

(124) .sup.1H NMR (250 MHz, CDCl.sub.3) δ (ppm): 6.17 (s, 1H), 5.56 (s, 1H), 4.60 (broad s, 1H), 4.24-4.16 (q, J=7.1 Hz, 2H), 3.17-3.10 (m, 2H), 2.30-2.36 (m, 2H), 1.72-1.60 (m, 2H), 1.44 (s, 9H), 1.30 (t, J=7.1 Hz, 3H).

(125) ESI-MS m/z calc. 257.3, found 258.7 [M+1]+. Retention time: 5.12 min.

Step 3: Synthesis of ethyl 2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoate (35)

(126) ##STR00278##

(127) To a stirring solution of 5-tert-butoxycarbonylamino-2-methylene-pentanoic acid ethyl ester (16.95 g, 65.87 mmol) and 2-nitropropane (29.4 g, 330.0 mmol) in anhydrous acetonitrile (250 mL) under nitrogen atmosphere was added 1,8-diazabicyclo[5.4.0]undec-7-ene (12.03 g, 79.0 mmol), and the reaction mixture was heated to 90° C. for 2 h. The reaction mixture was concentrated and the residue was extracted with ethyl acetate (400 mL). The organic layer was washed with 5% aqueous potassium bisulfate solution (2×300 mL) followed by brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The product was purified by silica gel column chromatography using 0-25% hexanes-acetone to afford 2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid ethyl ester (20.65 g, 90%) as a yellow oil.

(128) .sup.1H NMR (250 MHz, CDCl.sub.3) δ (ppm): 4.51 (broad s, 1H), 4.17-4.08 (q, J=7.1 Hz, 2H), 3.13-3.08 (m, 2H), 2.45-2.29 (m, 2H), 2.17-2.04 (m, 1H), 1.73-1.64 (m, 1H), 1.58-1.36 (m, 18H), 1.25 (t, J=7.1 Hz, 3H).

(129) ESI-MS m/z calc. 346.4, found 347.3 [M+1]. Retention time: 5.65 min.

Step 4: Synthesis of 2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoic acid ((f)-34)

(130) ##STR00279##

(131) To a mixture of 2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid ethyl ester (5 g, 14.43 mmol) in ethanol (20 mL) under nitrogen atmosphere was added 10% w/v NaOH (7 mL, 17.50 mmol), and the reaction mixture was heated to 50° C. After 5 h an additional 0.7 mL of 10% w/v NaOH was added. After heating for an additional 2 h, LC showed complete reaction. 20 mL of water was added to the reaction mixture and the mixture was concentrated to remove EtOH. 15 mL of IPAc was added. After mixing, the layers were separated and the aqueous layer was made acidic with 6 M HCl (pH 2-3). 20 ml of IPAc was added. After mixing, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid.

(132) The crude product from above was dissolved in 30 mL of IPAc. Dicyclohexylamine (2.6 mL, 13.05 mmol) was added dropwise via addition funnel. Crystallization initiated upon stirring. After stirring the slurry for several h, the solid was collected by filtration and washed with IPAc (2×7 mL). The salt was dried in a vacuum oven at 50° C. with a N.sub.2 bleed to afford 6.37 g of 2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid dicyclohexylammonium salt (88% for 2 steps).

(133) The salt was then slurried in 40 mL of IPAc. 20 mL of 10% aq w/v citric acid was added. The mixture was stirred vigorously until all solids dissolved. The layers were then separated and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. 50 mL of heptane was added and the mixture was concentrated. 40 mL of heptane was added to the solid and the slurry was stirred at ambient temperature. After stirring the slurry for several hours, the solid was collected by filtration and washed with heptane (2×8 mL). The product was dried in a vacuum oven at 50° C. with a N.sub.2 bleed to afford 3.27 g of 2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid (71% overall for the process).

Step 5: Synthesis of (R)-2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoic acid

(134) ##STR00280##

(135) Initial Crystallization: To a 100 mL flask containing 2-{3-[(tert-butoxycarbonyl)amino]propyl}-4-methyl-4-nitropentanoic acid (5 g, 15.705 mmol, 1 equiv) in CH.sub.3CN (25 mL, 0.628 M, 5 Vols), (S)-(−)-α-methylbenzylamine (0.952 g, 1.012 mL, 7.852 mmol, 0.5 equiv) was added. Stirred at ambient temperature, the mixture initially turned clear and then became a slurry within 5-10 min.

(136) The mixture was heated to 75° C. and held at 71-75° C. for 1 h, then cooled to 60° C. and held at 60° C. for 1 h. Then the mixture was cooled to 50° C., and was seeded with ˜25 mg of (R)-2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoic acid. The mixture became cloudy, and after 1 hr it was cooled to 40° C., and the resulting slurry was held at 40° C. for 1 hr, then cooled to ambient temperature and stirred overnight. The slurry was collected by filtration, rinsed with ACN (3×3 mL), and dried under vacuum oven at 40° C. overnight with a N.sub.2 bleed. 2.27 g was obtained (TY=3.45 g, 65%). The enantiomer ratio was 95:5 [% (AUC)]. The mother liquor ratio was 26:74.

(137) 1.sup.st Recrystallization: In a 50 mL of RBF, (1R)-1-phenylethanaminium 2-{3-[(tert-butoxycarbonyl)amino]propyl}-4-methyl-4-nitropentanoate (2.22 g, 5.051 mmol, 1 equiv) in CH.sub.3CN (15.54 mL, 0.325 M, 7 Vols). Mixture heated to 75° C., mixture became homogeneous at 66° C., hold at 71-75° C. for 1 h. Then cool to 60° C., slurry formed. Hold at 60° C. for 1 h. Cool to 50° C. and hold for 1 h. Cool to 40° C. Hold at 40° C. for 1 hr and then cool to ambient stirring overnight. Solid was collected by filtration and dried over the vacuum oven at 40° C. with N.sub.2 bleed overnight to afford 2.056 g of product as white solid (92%). The enantiomer ratio was 97:3 [% (AUC)]. The mother liquor ratio was 25:75.

(138) 2.sup.nd Recrystallization: To a 100 mL round-bottomed flask was added (1R)-1-phenylethanaminium 2-{3-[(tert-butoxycarbonyl)amino]propyl}-4-methyl-4-nitropentanoate (2 g, 4.55 mmol, 1 equiv) in CH.sub.3CN (16 mL, 0.284 M, 8 Vols). The mixture was heated to 75° C. The mixture became homogeneous at >66° C., then was held at 71-75° C. for 1 h. The mixture was then allowed to cool to 65° C. A slurry formed and was held for 1 h. Then it was cooled to 60° C. and held for 1 h, then cooled to 55° C. and held for 1 h, then cooled to 50° C. and held for 1 h, then cooled to 45° C. and held for 1 h, then cooled to ambient and stirred overnight. The solid was collected by filtration and dried in a vacuum oven at 40° C. with a N.sub.2 bleed overnight to afford 1.92 g of product as white solid (96%, 57% overall). The enantiomer ratio was 99:1 [% (AUC)]. The mother liquor ratio was 53:47.

Step 6: Synthesis of tert-butyl (R)-(4-(hydroxymethyl)-6-methyl-6-nitroheptyl)carbamate

(139) ##STR00281##

(140) CDI (305.7 mg, 1.885 mmol) was added to a solution of (R)-2-[3-(tert-butoxycarbonylamino)propyl]-4-methyl-4-nitro-pentanoic acid (500 mg, 1.571 mmol) in THF (1.500 mL) at room temperature. The mixture was stirred at ambient temperature. CDI activation of carboxylic acid was checked using n-butylamine in ACN. UPLC was checked at 80 min, 3 h, and 4 h.

(141) This reaction mixture was then transferred over 15 min to a solution of NaBH.sub.4 (178.3 mg, 188.7 μL, 4.713 mmol) in a mixture of THF (1.000 mL) and H.sub.2O (625.0 μL) at 0-5° C. The addition was exothermic. The mixture was stirred for 90 min at ambient temperature. UPLC showed the starting material was fully consumed.

(142) EtOAc (2.5 mL) and aqueous citric acid (approximately 2.415 g, 1.450 mL, 12.57 mmol) (in 2.5 mL of water) was added to quench the reaction. The layers were separated. The pH of the aqueous layer was 3. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated by rotary evaporation (80 mbar, 20° C. bath temp.) MTBE (5 mL) was added to the crude product and was washed with 1.5 mL of Sat. bicarb/water (1:1), at which point the aqueous layer pH was 5. The wash was repeated, at which point the aqueous layer pH became 7. The MTBE layer was dried over Na.sub.2SO.sub.4 and concentrated by rotary evaporation (300-150 mbar, 20° C. bath temp.) and used for the next step reaction without further purification.

Step 7: Synthesis of (R)-2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentyl 4-methylbenzenesulfonate

(143) ##STR00282##

(144) To the mixture of (R)-tert-buty N-[5-hydroxy-4-(2-methyl-2-nitropropyl)pentyl]carbamate (480 mg, 1.577 mmol, 1 equiv), triethylamine (0.319 g, 0.443 mL, 3.154 mmol, 2 equiv) and trimethylamine hydrochloride (0.154 g, 1.608 mmol, 1.02 equiv) in 2-MeTHF (3.5 mL, 0.451 M, 7.292 Vols), was added p-toluenesulfonyl chloride (0.451 g, 2.365 mmol, 1.5 equiv) at 0-5° C. The reaction was stirred at this temperature for 1 h, then warmed to ambient temperature and stirred at ambient temperature for another 3 h. By UPLC, the starting material was fully consumed. The reaction mixture was washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The crude was purified by column chromatography eluting with EtOAc/Hexane.

Step 8: Synthesis of tert-butyl (R)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate

(145) ##STR00283##

(146) To the solution of (R)-tert-butyl N-(6-methyl-4-{1[(4-methylbenzenesulfonyl)oxy]methyl}-6-nitroheptyl)carbamate (0.55 g, 1.103 mmol, 1 equiv) in MeTHF (9 mL, 0.123 M, 16.364 Vols) was added potassium carbonate (0.153 g, 1.103 mmol, 1 equiv) and Raney nickel (0.13 g, 1.103 mmol, 1 equiv). The mixture was degassed (vacuum) then purged with a hydrogen balloon (3 times). The reaction was heated to 78° C. The reaction mixture was cooled to room temperature and filtered through celite, and the cake was washed with MeTHF (50 mL). The filtered solution was washed with water, some product went to water layer (pH 5-6), the water layer was re-extracted with MeTHF. The combined MeTHF layer was dried over Na.sub.2SO.sub.4 and concentrated on rotovap. After drying under house vacuum overnight, 640 mg of crude product was obtained as an oil and was used without further purification.

Step 9: Synthesis of (R)-2-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)isoindoline-1,3-dione

(147) ##STR00284##

(148) A method for preparing (R)-2-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)isoindoline-1,3-dione from tert-butyl (R)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate is shown in the scheme above.

Step 10: Synthesis of (R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide

(149) ##STR00285##

(150) In a 3 necked 1 L round bottom flask, (R)-2-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)isoindoline-1,3-dione (38.98 g, 136.1 mmol, 1.03 equiv), 6-bromo-2-fluoronicotinamide (28.91 g, 132.0 mmol, 1 equiv), and MeCN (202 mL, 7 vol) were added followed by K.sub.2CO.sub.3 (−325 mesh, 21.16 g, 153.1 mmol, 1.16 equiv). The mixture was heated to 40° C. and the reaction was monitored by LC analysis. The reaction went to completion after 17 h. The reaction mixture was cooled down to ambient temperature. 300 mL (10.3 vol) of water was added through an addition funnel to afford a slurry. The resulting solid was collected by filtration. The solid was washed with water/MeCN (½, 2×40 mL, 1.4 vol) then dried by vacuum oven at 45° C. to afford (R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (56.5 g 88%).

Example 9: Synthesis of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (50)

(151) ##STR00286##

Step 1: Synthesis of perfluorophenyl 6-fluoropyridine-2-sulfonate

(152) ##STR00287##

(153) To a solution of 2,3,4,5,6-pentafluorophenol (33.21 g, 180.4 mmol) in iPrOAc (175 mL) was added aq KHCO.sub.3 (approximately 90.30 mL of 20% w/v, 180.4 mmol). The mixture was stirred at ambient temperature for 10 min. A solution of 6-fluoropyridine-2-sulfonyl chloride (35.29 g, 180.4 mmol) in iPrOAc (25 mL) was then added while keeping the temperature below 20° C. The reaction mixture was allowed to stir at ambient temperature for 1 hr to complete the reaction. The aqueous layer was removed, and the organic layer was washed with water (50 mL), dried over Na.sub.2SO.sub.4, then concentrated by rotary evaporation to remove most of solvent and precipitate a white solid. Heptane (70 mL) was added and the slurry was stirred at ambient temperature. The solid was collected by filtration, rinsed with heptane (30 mL), and dried under vacuum to give 58.76 g of perfluorophenyl 6-fluoropyridine-2-sulfonate as a white solid. The mother liquor was concentrated by rotary evaporation, then 1 mL (iPrOAc)/20 mL (Heptane) was added and stirred at ambient temperature overnight. The resulting solid was collected and dried under vacuum oven at ambient temperature overnight with a N.sub.2 bleed to give 0.87 g as a second crop. In total, 59.63 g (96% yield) of perfluorophenyl 6-fluoropyridine-2-sulfonate was obtained.

(154) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.46 (q, J=7.7 Hz, 1H), 8.20 (dd, J=7.5, 2.0 Hz, 1H), 7.84 (dd, J=8.3, 2.2 Hz, 1H).

(155) .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −64.25 (s, 1F), −152.20-−152.69 (m, 2F), −154.84 (t, J=23.3 Hz, 2F), −161.00-−161.74 (m, 1F).

Step 2: Synthesis of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (50)

(156) ##STR00288##

(157) A solution of lithium tert-butoxide (1,905.13 g, 2.20 equiv, 20% w/w in THF) was added to a mixture of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (1,050 g, 1.00 equiv) and perfluorophenyl 6-fluoropyridine-2-sulfonate (890.93 g, 1.20 equiv) in 2-MeTHF (10.5 L, 10.0 vol), keeping the internal temperature below −2° C. The mixture was stirred at −10° C. until the reaction was complete (typically 0.5 h). A solution of aq HCl (5.25 L, 5 vol, 1 N) was added while keeping the internal temperature <20° C. 2-MeTHF (5.0 L, 5 vol) was then added to the reactor at ambient temperature and then the phases were allowed to separate. The lower aqueous layer was discarded. The organic phase was washed with water (5 vol) then concentrated to 5 volumes under vacuum keeping the temperature below 50° C. 2-MeTHF (10.0 L, 10 vol) was added and again the mixture concentrated to 5 volumes. 2-MeTHF (5 vol) was added and the heterogenous mixture was heated to 70° C. with agitation until complete dissolution occurred. The mixture was then cooled linearly to 45° C. over 6 h then held at 45° C. for 6 h. The mixture was then cooled to 25° C. over 2 h then heptane (10.0 L, 10 vol) was added to the mixture over 3 h. The mixture was drained from the reactor and the solids were isolated. The reactor and filter cake were then washed twice with a mixture of 2-MeTHF (2.0 L, 2 vol) and heptane (2.0 L, 2 vol). The solids were dried under vacuum at 45° C. to afford (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide.

(158) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.05 (s, 1H), 8.37 (q, J=7.8 Hz, 1H), 8.11 (dd, J=7.4, 1.9 Hz, 1H), 7.95-7.88 (m, 2H), 7.88-7.81 (m, 2H), 7.59 (dd, J=8.1, 2.4 Hz, 2H), 6.78 (d, J=7.9 Hz, 1H), 3.59 (t, J=6.8 Hz, 2H), 2.45 (dd, J=8.8, 3.9 Hz, 2H), 2.17 (s, 1H), 1.87 (dd, J=11.9, 5.5 Hz, 1H), 1.56 (dddd, J=22.3, 16.7, 8.9, 4.1 Hz, 2H), 1.47 (s, 3H), 1.44 (s, 3H), 1.35 (t, J=12.1 Hz, 1H), 1.21 (ddd, J=13.3, 10.5, 5.4 Hz, 1H), 1.00 (dtd, J=14.1, 9.4, 5.7 Hz, 1H).

Example 10: Synthesis of (14S)-8-bromo-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (40)

(159) ##STR00289##

Step 1: Alternative Synthesis of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (50)

(160) ##STR00290##

(161) 6-Fluoropyridine-2-sulfonyl chloride (529 g, 340 mL, 2.71 mol) was added to a solution of a 2:1 ratio of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide in toluene (1.20 kg, 2.26 mol; 91.2% potency) in 2-MeTHF (6.56 L; 6 VolEq) at 0-5° C. then lithium 2-methylbutan-2-olate (t-OAmLi; 1.22 kg of 40% w/w, 1.67 L of 40% w/w, 5.19 mol; 2.3 equiv) was added while maintaining the reaction temperature between 5-10° C. After the addition was completed, the reaction solution was stirred at 0-10° C. until the reaction is complete (HPLC shows <1% AUC (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide remains). The reaction solution was advanced to the next step without any further processing.

Step 2: Synthesis of (S)-2-((3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamoyl)benzoic acid

(162) ##STR00291##

(163) The reaction solution containing (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide from the preceding step was cooled and maintained below 10° C. when a solution of LiOH.H.sub.2O (284 g, 6.77 mol; 3 equiv) in water (2.19 L; 2 VolEq) was added. The biphasic mixture was stirred at 5-15° C. until the reaction was completed (about 2 h). While maintaining the reaction temperature below 10° C., 2 M HCl (5.64 L, 11.3 mol; 5 equiv) was added dropwise over ˜1 h. The pH of the aqueous phase was about 2. The phases were separated then the organic phase was concentrated to a minimum volume removing most of the 2-MeTHF (40° C./150-70 torr). The reaction mixture was advanced to the next step without any further processing.

Step 3: Synthesis of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (48)

(164) ##STR00292##

(165) The concentrate containing (S)-2-((3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamoyl)benzoic acid from the preceding step was diluted with CH.sub.3CN (6.56 L; 6 VolEq) and water (3.83 L; 2 VolEq) then oxalic acid (508 g, 5.64 mol; 2.5 equiv) was added and the resultant solution was heated at 60° C. until the reaction was complete (about at least 4 h). The solution was cooled to 0-10° C. then a solution of K.sub.2CO.sub.3 (2.18 kg, 15.8 mol; 7 equiv) in water (3.83 L; 3.5 VolEq) was added dropwise while maintaining the reaction temperature below 10° C. The solid was collected by filtration. The damp filter-cake was washed consecutively with water (2×2.2 L; 2 VolEq) and then i-PrOH (2×600 mL; 0.5 VolEq), air-dried with suction, and vacuum-dried (50° C./30 torr) to afford (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (959 g; 83% for 3 steps; >98% AUC) as a fine, white powder.

(166) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.09 (q, J=7.9 Hz, 1H), 7.83 (dd, J=7.5, 2.2 Hz, 1H), 7.67 (s, 3H), 7.39 (d, J=7.6 Hz, 1H), 7.23 (dd, J=8.2, 2.4 Hz, 1H), 6.58 (d, J=7.6 Hz, 1H), 3.20-2.99 (m, 2H), 2.81 (td, J=7.2, 4.7 Hz, 2H), 2.08 (dh, J=15.3, 7.0 Hz, 1H), 1.84 (dd, J=11.8, 5.7 Hz, 1H), 1.54 (q, J=7.6 Hz, 2H), 1.48 (s, 3H), 1.47 (s, 3H), 1.37 (t, J=11.9 Hz, 1H), 1.26 (ddd, J=29.1, 13.8, 7.4 Hz, 2H).

Step 4: Synthesis of (14S)-8-bromo-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (40)

(167) ##STR00293##

(168) A mixture of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (950 g, 1.85 mol) and Na.sub.2CO.sub.3 (392 g, 3.69 mol; 2 equiv) in DMSO (7.60 L; 8 VolEq) was heated at 85° C. until the reaction was completed (˜6 h). The suspension was cooled to <15° C. and diluted with MeTHF (19.0 L; 20 VolEq). Water (13.3 L) was added slowly while maintaining the reaction temperature <15° C. While maintaining the reaction temperature <15° C., 2 M HCl (4.62 L, 9.24 mol; 5 equiv) was added (pH ˜2). The phases were separated and the organic phase was washed twice with water (9.50 L; 10 VolEq) containing NaCl (190 g; 2 wt %). The organic phase was concentrated to a minimum volume (45° C./180 torr) and chased with i-PrOAc (2-3×500 mL) to remove the MeTHF. The concentrate was backfilled with i-PrOAc (3.800 L; 4 VolEq) and agitated at 45° C. until crystallization occurred. (The mixture may be seeded with (14S)-8-bromo-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione if necessary). The suspension was aged with agitation for at least 30 min and then allowed to cool to 20° C. After aging at 20° C. for at least 2 h, the solid was collected by filtration. The filter-cake was washed with 1:1 i-PrOAc/MTBE (500-mL), air-dried with suction, and vacuum-dried (40-55° C./<100 torr/N.sub.2 bleed) to afford (14S)-8-bromo-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione.0.8 i-PrOAc (830 g; 78% yield corrected for i-PrOAc solvate) as a white powder with a slight yellow tint.

(169) A second crop was obtained by concentrating the filtrate to −400 mL total volume. The mixture was then seeded and aged at 15-20° C. The solid was collected by filtration. The filter-cake was washed successively with 1:1 i-PrOAc/MTBE (200 mL) and MTBE (100 mL), air-dried with suction, and vacuum-dried (55° C./<100 torr/N.sub.2 bleed) to afford (14S)-8-bromo-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione.0.67 i-PrOAc (113 g; 11% corrected yield) as a pale yellow solid.

(170) .sup.1H NMR (400 MHz, Chloroform-d) δ 9.13 (s, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.54 (dd, J=8.4, 7.3 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 4.99 (hept, J=6.3 Hz, 1H), 4.57 (d, J=8.8 Hz, 1H), 4.02-3.85 (m, 1H), 3.27-3.09 (m, 2H), 2.96 (t, J=10.2 Hz, 1H), 2.35 (p, J=9.5 Hz, 1H), 2.02 (s, 3H), 1.95 (dd, J=12.1, 6.7 Hz, 1H), 1.72-1.59 (m, 6H), 1.58 (s, 3H), 1.55 (s, 3H), 1.43 (d, J=40.1 Hz, 1H), 1.23 (d, J=6.3 Hz, 5H).

Example 11: Synthesis of (14S)-8-bromo-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (40)

(171) ##STR00294##

(172) A mixture of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (40.2 g, 78.2 mmol) and K.sub.2CO.sub.3 (−325 mesh, 27.0 g, 195.5 mmol; 2.5 equiv) in DMSO (0.4 L; 10 VolEq) was heated at 70° C. until the reaction was completed. The suspension was cooled to <15° C. and diluted with IPAc (0.3 L; 7.5 VolEq). While maintaining the reaction temperature <15° C., 1 M HCl (0.41 L, 406.8 mmol; 4.3 equiv) was added (pH ˜2).

(173) After aging at 20° C. for at least 2 h, the solid was collected by filtration. The filter-cake was washed with water (4×50-mL) followed by IPAc (2×75 mL), air-dried with suction, and vacuum-dried (45° C./<100 torr/N.sub.2 bleed) to afford (14S)-8-bromo-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione.1 DMSO (29 g; 73% yield corrected for DMSO solvate).

(174) .sup.1H NMR (400 MHz, Chloroform-d) δ 9.13 (s, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.54 (dd, J=8.4, 7.3 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 4.99 (hept, J=6.3 Hz, 1H), 4.57 (d, J=8.8 Hz, 1H), 4.02-3.85 (m, 1H), 3.27-3.09 (m, 2H), 2.96 (t, J=10.2 Hz, 1H), 2.5 (s, 6H, DMSO), 2.35 (p, J=9.5 Hz, 1H), 2.02 (s, 3H), 1.95 (dd, J=12.1, 6.7 Hz, 1H), 1.72-1.59 (m, 6H), 1.58 (s, 3H), 1.55 (s, 3H), 1.43 (d, J=40.1 Hz, 1H), 1.23 (d, J=6.3 Hz, 5H).

Example 12A: Synthesis of (14S)-8-[3-(2-{dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound I)

(175) ##STR00295##

(176) A mixture of (14S)-8-bromo-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (120 g of 86% w/w with IPAc [103.2 g (14S)-8-bromo-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione], 0.21 mol, 1 equiv), 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole (42.6 g, 0.21 mol, 1 equiv), K.sub.2CO.sub.3 (325 mesh, 63.4 g, 0.46 mol, 2.2 equiv), CuI (3.3 g, 17.2 mmol, 0.083 equiv) and BuOAc (740 mL, 7.2 vol based on active (14S)-8-bromo-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione) was stirred at ambient temperature. DMF (300 mL, 2.9 vol) and N,N′-dimethylcyclohexane-1,2-diamine (14.6 g or 16.2 ml, 0.1 mol, 0.49 equiv) were then added and the reactor contents purged with N.sub.2. The mixture was then heated to 120° C. until the reaction is completed (˜4 h).

(177) The mixture was allowed to cool to ambient then 10% aq w/v oxalic acid (860 mL, 0.96 mol, 4.6 equiv) was added dropwise. The mixture was stirred for at least 1 h then the solids were removed by filtration. The removed solids were washed with IPAc (2×120 mL). The organic layer was isolated then washed with 8% aq w/v trisodium citrate (600 mL) then 1:1 v/v water/brine (400 mL). The organic layer was filtered through a pad of Celite. The filter pad was washed with IPAc (150 mL) and the filtrate concentrated. 1-PrOH (800 mL of 7.8 vol) was added and the mixture concentrated. This step was repeated one more time then toluene (800 mL) was added and the mixture concentrated. This step is repeated one more time to afford a thick slurry. The crude mixture was concentrated to volume of 300 mL (2.9 vol) of toluene. (The mixture was seeded with Compound I Form A if the mixture is homogeneous). After stirring the slurry overnight, the solid was collected by filtration washing the solid with toluene (2×100 mL, 0.97 vol). The solid is dried under vacuum to afford Compound I Form A as a white/off-white solid (107.0 g, 83%,94.5% (AUC) HPLC purity).

(178) Compound I Form A [22.2 g, 94.6% (AUC)] was suspended in toluene (440 mL, 20 vol based on Compound I) and the mixture heated to reflux for at least 2 h. The mixture was cooled over 8 h to ambient temperature then stirred overnight. The solid was collected by filtration washing the solid with toluene (40 mL, 1.8 vol). The solid was dried under vacuum with a nitrogen bleed at 50° C. until the loss on drying is NMT 1.0% to afford Compound I Form A as a white/off-white solid (18.8 g, 84%, 96.8% (AUC) HPLC purity).

(179) Compound I Form A [17.5 g, 97.0% (AUC)] was suspended in toluene (350 mL, 20 vol) and the mixture heated to reflux. After holding at reflux for at least 2 h, the mixture was cooled over 8 h to ambient temperature then stirred at ambient temperature overnight. The solid was collected by filtration washing the solid with toluene (40 mL, 1.8 vol) then dried under vacuum to afford Compound I Form A as a white/off-white solid (15.7 g, 89%,98.4% (AUC) HPLC purity).

(180) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.52 (s, 1H), 8.21 (d, J=2.9 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.12-6.83 (m, 3H), 6.72 (d, J=8.5 Hz, 1H), 6.09 (d, J=2.8 Hz, 1H), 4.22 (td, J=6.8, 2.3 Hz, 2H), 4.04-3.84 (m, 1H), 3.16 (s, 1H), 2.96 (d, J=13.1 Hz, 1H), 2.70 (d, J=11.3 Hz, 1H), 2.13 (s, 1H), 1.84 (dq, J=20.2, 6.6, 5.9 Hz, 4H), 1.70-1.40 (m, 10H), 1.32 (q, J=12.2 Hz, 1H), 0.90-0.75 (m, 4H), 0.65 (dd, J=8.6, 4.2 Hz, 2H), 0.51 (dd, J=8.5, 4.2 Hz, 2H).

Example 12B: Alternative Synthesis of (14S)-8-[3-(2-{dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound I)

(181) ##STR00296##

(182) A mixture of (14S)-8-bromo-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (110 g, 182.441 mmol, 1.00 equiv, iPrOAc solvate), 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole (48.447 g, 237.174 mmol, 1.3 equiv) and MEK (8 volumes) was heated to 40° C. then degassed with N.sub.2. tBuXphos Pd G3 (1.922 g, 2.372 mmol, 1.25 mol %) was then added to the mixture. A degassed solution of MTBD (67.034 g, 428.737 mmol, 2.35 equiv) in MEK (2.00 vol) was then added to the reactor over 1 h while maintaining 40° C. The reaction was then stirred at 40° C. until completed (about 2 h) then cooled to 20° C. An aqueous work-up was then performed with 1M HCl then the organic layer was stirred with Silia Met S Thiol (66 g, 60% w/w relative to (14S)-8-bromo-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione) at 50° C. for 6 h. The mixture was cooled to 20° C. then filtered through Celite then concentrated under vacuum. The solvent was swapped by vacuum distillation to toluene (3 vol) then cooled to 20° C. and stirred for at least 3 h. The solid was isolated by filtration then dried under vacuum to afford Compound I Form A (92 g, 81% yield).

Example 13: Synthesis of benzyl (S)-(3-(1-(6-bromo-3-carbamoylpyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (45)

(183) ##STR00297##

(184) A stirred suspension of 6-bromo-2-fluoronicotinamide (40.0 g, 183 mmol), benzyl (S)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate•HCl (65.7 g, 201 mmol; 1.1 equiv), and K.sub.2CO.sub.3 (30.3 g, 219 mmol) in acetonitrile (260 mL) was warmed at 40° C. until the reaction was complete (˜20 h) then cooled to ambient temperature. Water (480 mL) was slowly added and the resulting solid was collected by filtration. The filter-cake was washed with 2:1 water:CH.sub.3CN (2×120 mL), then dried to afford benzyl (S)-(3-(1-(6-bromo-3-carbamoylpyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (86.8 g; 97%; 99.0% AUC) as an off-white powder.

(185) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.80 (d, J=2.3 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.39-7.25 (m, 7H), 6.68 (d, J=7.7 Hz, 1H), 5.01 (s, 2H), 3.29-3.10 (m, 2H), 3.00 (q, J=6.6 Hz, 2H), 2.19 (s, 1H), 1.90 (dd, J=11.8, 5.6 Hz, 1H), 1.53 (s, 3H), 1.49 (s, 3H), 1.47-1.24 (m, 5H).

(186) UPLC-MS: M+1=489/491 (conforms).

Example 14: Alternative Synthesis of (14S)-8-[3-(2-{dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound I)

(187) ##STR00298##

Step 1: Synthesis of benzyl (S)-(3-(1-(3-carbamoyl-6-(3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (51)

(188) ##STR00299##

(189) A suspension of benzyl (S)-(3-(1-(6-bromo-3-carbamoylpyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (85.0 g, 174 mmol), 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole (42.57 g, 208.4 mmol, 1.2 equiv), K.sub.2CO.sub.3 (52.8 g, 382 mmol, 2.2 equiv), and (1R,2R)-N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (19.8 g, 21.9 mL, 139 mmol, 0.8 equiv) in DMF (425 mL) was purged with N.sub.2 for 20 min. CuI (3.3 g, 17 mmol, 0.1 equiv) was added and the mixture purged for an additional 5 min, then heated at 90° C. until the reaction was completed (˜3.5 h). Next the reaction was cooled at ambient temperature. 2-MeTHF (850 mL) and 0.5 M NH.sub.4OH (452 mL, 226 mmol) were added and the uppermost organic phase was isolated then washed successively with 0.5 M NH.sub.4OH (2×174 mL, 86.8 mmol), 0.5 M HCl (347 mL, 174 mmol), water (150 mL)/brine (50 mL), and sat. NaHCO.sub.3(50 mL). The solution was dried (Na.sub.2SO.sub.4) then concentrated to an oil. CH.sub.3CN (255 mL) was added then removed under vacuum to afford a tan solid. The solid was slurried with CH.sub.3CN (255 mL) at 40° C. for 20 min to give a suspension, which was then cooled to room temperature and stirred. The solid was isolated by filtration then dried to afford benzyl (S)-(3-(1-(3-carbamoyl-6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (70.4 g; 66%; 95.8% AUC) as a white powder.

(190) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.19 (d, J=2.7 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.42-7.20 (m, 7H), 6.84 (d, J=8.0 Hz, 1H), 6.05 (d, J=2.7 Hz, 1H), 5.01 (s, 2H), 4.20 (t, J=6.7 Hz, 2H), 3.32 (t, J=10.4 Hz, 1H), 3.19 (t, J=8.8 Hz, 1H), 3.01 (q, J=6.5 Hz, 2H), 2.21 (s, 1H), 1.94 (dd, J=11.9, 5.6 Hz, 1H), 1.81 (q, J=6.6 Hz, 2H), 1.61 (s, 3H), 1.57 (s, 3H), 1.53-1.23 (m, 6H), 0.90-0.77 (m, 4H), 0.67-0.60 (m, 2H), 0.53-0.46 (m, 2H).

Step 2: Synthesis of benzyl (S)-(3-(1-(6-(3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (52)

(191) ##STR00300##

(192) A solution of benzyl (S)-(3-(1-(3-carbamoyl-6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (68.0 g, 111 mmol) in 2-MeTHF (408 mL, 6 VolEq) was cooled to 0-5° C., then 6-fluoropyridine-2-sulfonyl chloride (29.2 g of 92.9% w/w, 139 mmol; 1.25 equiv) in 2-MeTHF (136 mL, 2 VolEq) was added. A 40% w/w heptane solution of lithium 2-methylbutan-2-olate (82.3, 255 mmol; 2.3 equiv) was added slowly, maintaining the reaction temperature between 0-5° C. The solution was stirred until the reaction was complete (30 min), then EtOAc (408 mL, 6 VolEq) and a solution of NaHSO.sub.4 (32.0 g, 266 mmol, 2.4 equiv) in water (272 mL; 4 VolEq) were added. The organic phase was isolated then washed with water (272 mL; 4 VolEq), dried (Na.sub.2SO.sub.4), and concentrated to a brown semi-solid. MIBK (238 mL; 3.5 VolEq) was added and the mixture was heated to 70° C., then seeded with crystalline benzyl (S)-(3-(1-(6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate, then allowed to cool to ambient temperature, then stirred for 2 h. The solid was collected by filtration then dried to afford benzyl (S)-(3-(1-(6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (53.7 g, 63%; 97.5% AUC) as a white powder.

(193) Additional product was obtained as a 2.sup.nd crop after a SiO.sub.2 plug filtration followed by crystallization from i-PrOH/MIBK to afford benzyl (S)-(3-(1-(6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (14.4 g; 17%; 92.5% AUC) as an off-white powder.

(194) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.34 (q, J=7.8 Hz, 1H), 8.13 (dd, J=7.4, 2.0 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.59 (dd, J=8.3, 2.3 Hz, 1H), 7.37 (d, J=4.2 Hz, 4H), 7.34-7.21 (m, 2H), 6.94 (d, J=8.3 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 5.05 (s, 2H), 4.22 (t, J=6.7 Hz, 2H), 3.01 (hept, J=6.7 Hz, 2H), 2.46 (dd, J=10.4, 7.0 Hz, 1H), 2.13 (s, 1H), 1.89 (dd, J=11.8, 5.5 Hz, 1H), 1.81 (q, J=6.6 Hz, 2H), 1.54 (s, 6H), 1.47 (t, J=6.5 Hz, 1H), 1.34 (td, J=13.1, 12.6, 6.7 Hz, 3H), 1.17 (dt, J=16.1, 5.2 Hz, 1H), 0.97 (dt, J=13.4, 8.8 Hz, 1H), 0.89-0.75 (m, 4H), 0.71-0.57 (m, 2H), 0.56-0.41 (m, 2H).

(195) .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −65.73.

Step 3: Synthesis of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide((S)-53)

(196) ##STR00301##

(197) A suspension of benzyl (S)-(3-(1-(6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (40.0 g, 51.8 mmol), ammonium formate (26.1 g, 415 mmol; 8 equiv), DABCO (116 mg, 1.03 mmol; 0.02 equiv), and 10% Pd on carbon (1.0 g, 0.94 mmol; 0.02 equiv) in MeOH (240 mL; 6 VolEq) was stirred at ambient temperature until the reaction was complete (˜70 min). The catalyst was removed by filtration and the filtrate concentrated under vacuum to an oil. The mixture was slurried in MeTHF (200 mL) and EtOAc (200 mL) at 40° C. then the solid was removed by filtration. The filter-cake was rinsed with 2-MeTHF (3×30 mL) then the combined filtrate and washings were concentrated under vacuum to afford (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (36.0 g; 102% of HCO.sub.2H salt; 96.2% AUC) as a white, granular powder which was used without further purification.

(198) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.15 (d, J=2.7 Hz, 1H), 8.11 (q, J=7.9 Hz, 1H), 7.86 (dd, J=7.4, 2.2 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.24 (dd, J=8.3, 2.4 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.01 (d, J=2.7 Hz, 1H), 4.20 (t, J=6.7 Hz, 2H), 3.15 (t, J=10.6 Hz, 1H), 3.06 (dd, J=10.9, 7.3 Hz, 1H), 2.82 (hept, J=7.2, 6.3 Hz, 2H), 2.08 (s, 1H), 1.81 (q, J=6.5 Hz, 2H), 1.55 (s, 5H), 1.51 (s, 3H), 1.47 (t, J=6.5 Hz, 1H), 1.42-1.27 (m, 3H), 1.26-1.15 (m, 1H), 0.83 (d, J=5.5 Hz, 4H), 0.64 (dd, J=8.5, 4.2 Hz, 2H), 0.50 (dd, J=8.5, 4.0 Hz, 2H).

Step 4: Synthesis of (14S)-8-[3-(2-{dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl}ethoxy)-H-pyrazol-1-yl]-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound I)

(199) ##STR00302##

(200) A mixture of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide•HCO.sub.2H (35.0 g, 51.2 mmol) and K.sub.2CO.sub.3 (21.2 g, 154 mmol; 3 equiv) in DMSO (350 mL; 10 VolEq) was heated at 90° C. under a N.sub.2 blanket for 6 h and then allowed to cool to RT. The suspension was diluted with EtOAc (525 mL; 15 VolEq) and water (280 mL; 8 VolEq). The phases were separated, and the aqueous phase extracted with EtOAc (210 mL). The combined organic phases were washed with a 20% w/v solution of citric acid (49.2 mL, 51.2 mmol) diluted in water (280 mL); the aqueous pH was 3-4. The organic phase was then washed with water (2×280 mL), dried (Na.sub.2SO.sub.4), and concentrated (40° C./30 torr) to afford crude Compound I (35.9 g; 114% theoretical yield; 94.9% AUC) as a pale orange foam.

(201) The crude product was dissolved in hot (105° C.) PhMe (210 mL; 6 VolEq); a yellow solution resulted at ˜40° C. The solution self-nucleated at −80° C. and gradual crystallization occurred. The reaction mixture remained a suspension at 105° C. The suspension was cooled to 20° C. at 10° C./h and allowed to stir overnight. The solid was collected by filtration and the filter-cake was washed with PhMe (2×20 mL). The damp solid was air-dried with suction and then vacuum-dried (50° C./300 torr/N.sub.2 bleed) to afford crystalline Compound I (25.3 g; 80%; 98.7% AUC) as a bright, white powder.

(202) .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.52 (s, 1H), 8.21 (d, J=2.9 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.12-6.83 (m, 3H), 6.72 (d, J=8.5 Hz, 1H), 6.09 (d, J=2.8 Hz, 1H), 4.22 (td, J=6.8, 2.3 Hz, 2H), 4.04-3.84 (m, 1H), 3.16 (s, 1H), 2.96 (d, J=13.1 Hz, 1H), 2.70 (d, J=11.3 Hz, 1H), 2.13 (s, 1H), 1.84 (dq, J=20.2, 6.6, 5.9 Hz, 4H), 1.70-1.40 (m, 10H), 1.32 (q, J=12.2 Hz, 1H), 0.90-0.75 (m, 4H), 0.65 (dd, J=8.6, 4.2 Hz, 2H), 0.51 (dd, J=8.5, 4.2 Hz, 2H).

(203) UPLC-MS: [M+1]=618.5 (conforms).

Example 15: Alternative Synthesis of (14S)-8-[3-(2-{dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound I)

(204) ##STR00303##

Step 1: Synthesis of benzyl (S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (47)

(205) ##STR00304##

(206) A reaction solution containing 6-fluoropyridine-2-sulfonyl chloride (459.5 mg, 2.349 mmol, 1.15 equiv), was diluted with 2-MeTHF (10 mL, 10 VolEq), and benzyl (S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (1.00 g, 2.043 mmol, 1.0 equiv) was added, then the mixture was cooled to 5° C. and lithium t-amoxide (40 w/w % solution in heptane, 1.20 g, 5.108 mmol, 2.5 equiv) slowly added via syringe in order to maintain an internal temperature of <7° C. Once the addition was complete, the reaction mixture was stirred and allowed to warm to room temperature and held until reaction was complete (˜1 h). The reaction mixture was cooled to <10° C. and aq 1M HCl solution (8.172 mL, 8.172 mmol, 4.0 equiv) was added, to bring the mixture to pH=1. The phases were separated and the organic phase was washed with water (5.000 mL, 5.0 VolEq), then washed with brine (3.000 mL, 3.0 VolEq). The organic phase was transferred to a flask and concentrated to solid benzyl (S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (1.38 g, 104.2% yield, not corrected for residual solvent).

(207) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.09 (s, 1H), 8.44-8.31 (m, 1H), 8.12 (d, J=7.2 Hz, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.41-7.22 (m, 5H), 6.78 (d, J=8.0 Hz, 1H), 5.04 (s, 2H), 3.87-3.71 (m, 2H), 3.52 (q, 1H), 3.09-2.91 (m, 2H), 2.11 (s, 1H), 2.01-1.68 (m, 1H), 1.46 (d, J=8.4 Hz, 6H), 1.39-1.24 (m, 4H).

Step 2: Alternative Synthesis of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (48)

(208) ##STR00305##

(209) To a reaction vessel stirring at room temperature was added water followed by sulfuric acid to prepare aqueous 9M H.sub.2SO.sub.4 (41.14 mL, 9.0 M, 370.2 mmol). To the resulting solution was added benzyl (S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)164yridine-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (8.0 g, 12.34 mmol, 1.0 equiv) and the resulting reaction mixture was stirred at 30° C. until the reaction was deemed complete. The reaction mixture was cooled >10° C. and basified with aq NaOH (aq 4M solution, aprox 100 mL, 400 mmol) and diluted with 2-MeTHF (160.0 mL, 20.0 VolEq), stirred at 20-25° C., and separated. The aqueous phase was re-extracted with 2-MeTHF (80.0 mL, 10.0 VolEq). The organic phases were combined and partially concentrated (4-8 VolEq) allowing product to crystallize out of solution. The mixture was then filtered the solid rinsed with 2-MeTHF (16.0 mL, 2.0 VolEq), and the solid dried in vacuo to afford (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (2.96 g, 45%), as off-white crystalline solid.

(210) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.08 (q, J=8.0 Hz, 1H), 7.83 (dd, J=7.3, 2.4 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.32 (d, J=5.1 Hz, 1H), 6.56 (d, J=7.6 Hz, 1H), 3.86-3.79 (m, 0H), 3.77-3.68 (m, 0H), 3.55 (td, J=8.0, 6.4 Hz, 0H), 3.03-2.87 (m, 2H), 1.97-1.89 (m, 0H), 1.86-1.77 (m, 1H), 1.46 (s, 6H), 1.30 (ddt, J=12.9, 5.3, 3.8 Hz, 2H), 1.14-1.07 (m, 2H).

Step 3: Alternative Synthesis of (14S)-8-bromo-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (40)

(211) ##STR00306##

(212) A mixture of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (2.80 g, 5.443 mmol, 1.0 equiv) in DMSO (28.00 mL, 10.0 VolEq) was stirred and added MgCl.sub.2 (518.2 mg, 5.443 mmol, 1.0 equiv) followed by addition of K.sub.2CO.sub.3 (1.881 g, 13.61 mmol, 2.50 equiv, 325 mesh) and stirred at 80° C. until complete (20 h). The mixture was cooled to 10° C., diluted with EtOAc (42.00 mL, 15.0 VolEq) and acidified with aq 1M HCl (32.66 mL, 32.66 mmol, 6.0 equiv), The aqueous phase was re-extracted with EtOAc (22.40 mL, 8.0 VolEq) and the organic phases combined and washed with water (22.40 mL, 8.0 VolEq), then twice with brine (8.400 mL, 3.0 VolEq). The solution was concentrated to afford 2.59 g (yield=96%) of (14S)-8-bromo-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione, as amber foam.

(213) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.63 (s, 1H), 7.67-7.44 (m, 2H), 7.06 (d, J=7.2 Hz, 1H), 6.73 (dd, J=17.6, 8.2 Hz, 2H), 4.86 (p, J=6.3 Hz, 1H), 3.87 (s, 1H), 3.09 (s, 1H), 2.94 (d, J=13.5 Hz, 1H), 2.61 (d, J=10.6 Hz, 1H), 2.11 (s, 1H), 1.90-1.68 (m, 1H), 1.55 (s, 2H), 1.42 (s, 2H), 1.36-1.23 (m, 1H), 1.17 (d, J=6.3 Hz, 6H).

Step 4: Alternative Synthesis of (14S)-8-[3-(2-{dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound I)

(214) ##STR00307##

(215) To a vessel was loaded DMF (17,500 mL, 7.0 VolEq), butyl acetate (17,500 mL, 7.0 VolEq), (14S)-8-bromo-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (2,500 g, 5,056.58 mmol, 1.00 equiv), and 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole (1,122.716 g, 5,056.58 mmol, 1.00 equiv). The mixture was stirred at room temperature. then added K.sub.2CO.sub.3 (325 mesh, 1,537.514 g, 11,124.477 mol, 2.2 equiv), CuI (79.931 g, 419.696 mmol, 0.083 equiv) and trans-cyclohexane-1,2-diamine (238.794 g, 1,678.785 mmol, 0.332 equiv). The mixture was heated to 120° C. until complete. then the mixture was cooled >30° C. and aq oxalic acid (27.0 L of 0.8 M aqueous solution prepared by mixing 2,094.236 g oxalic acid into 25,0000 mL water) was added to adjust the pH to >3. The resulting mixture was diluted by addition of isopropyl acetate (7,500 mL, 3.0 VolEq) and filtered through Celite washing with isopropyl acetate (2,500 mL, 1.0 VolEq). The filtrate layers were allowed to separate (slow). The organic phase was then washed with aqueous sodium citrate (8% solution, made from trisodium citrate 1,150.963 g, 4,459.904 mmol, 5.0 equiv dissolved in 15.0 L, 6.0 VolEq water), the organic phase was washed with brine (5.0 L, 2.0 VolEq of 10% w/w NaCl in water solution), the organic phase was filtered through Celite, and the Celite cake rinsed with isopropyl acetate (2.5 L, 1.0 VolEq). The organic phase was concentrated to a thick oil, that was diluted with toluene (50,000 mL, 20.0 VolEq), transferred to a reactor (reactor jacket at 60° C.) and stirred, then heated to reflux, held at reflux for 2 h, then cooled to 20° C. over 8 h, then filtered. The filter cake was washed with toluene (5.0 L, 2.0 VolEq) and dried in vacuo (50-55° C., vacuum) to afford Compound I (1,290 g, 41.296% yield) as a crystalline solid.

(216) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.49 (s, 1H), 8.20 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.58 (dd, J=8.5, 7.2 Hz, 1H), 7.06 (d, J=7.1 Hz, 1H), 6.97 (d, J=9.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.08 (d, J=2.7 Hz, 1H), 4.21 (td, J=6.6, 1.4 Hz, 2H), 3.92 (d, J=12.0 Hz, 1H), 3.15 (d, J=9.1 Hz, 1H), 2.95 (d, J=13.4 Hz, 1H), 2.71 (t, J=10.5 Hz, 1H), 2.12 (s, 1H), 1.83 (tq, J=14.8, 8.1, 6.7 Hz, 4H), 1.66-1.43 (m, 11H), 1.39-1.24 (m, 1H), 0.88-0.79 (m, 4H), 0.69-0.58 (m, 2H), 0.54-0.44 (m, 2H).

Example 16: Synthesis of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3)

(217) ##STR00308##

Step 1: Synthesis of 3-methylenetetrahydro-2H-pyran-2-one (5)

(218) ##STR00309##

(219) Step 1a: A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with sodium hydride (59.91 g of 60% w/w, 1.498 mol) followed by heptane (1.5 L) which provided a grey suspension. Stirring was commenced and the internal temperature was recorded at 19° C. The vessel was then charged with ethyl alcohol (3.451 g, 74.91 mmol) added via syringe, which resulted in gas evolution. The addition funnel was charged with a clear pale yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 h, which resulted in gas evolution and a gradual exotherm to 45° C. The resulting thick white suspension was then heated to 65° C. for 2 h and then allowed to cool to room temperature. The mixture continued to stir at room temperature overnight (about 10 h). The reaction mixture was vacuum filtered through a glass frit Buchner funnel (Medium porosity) under a stream of nitrogen. The filter cake was displaced and washed with heptane (2×250 ml) and pulled for a few minutes. The slightly heptane wet cake was transferred to a glass tray and dried in a vacuum oven at 45° C. for 15 h to provide a white solid (205 g, 1.36 mol, 91% yield) as the desired product (E)-(2-oxotetrahydropyran-3-ylidene)methanolate.

(220) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.99 (s, 1H), 3.90-3.83 (m, 2H), 2.09 (t, J=6.3 Hz, 2H), 1.57 (qd, J=6.4, 4.7 Hz, 2H).

(221) Step 1b: A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with (E)-(2-oxotetrahydropyran-3-ylidene)methanolate-Na salt (205 g, 1.366 mol) and tetrahydrofuran (1640 mL) which provided a white suspension. Stirring was commenced and the pot temperature was recorded at 19° C. The vessel was then charged with paraformaldehyde (136.6 g, 4.549 mol) added as a solid in one portion. The resulting suspension was heated to 63° C. and the condition was maintained for 15 h. The resulting white gelatinous mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. The remaining residue was partitioned with ethyl acetate (1000 ml), saturated sodium chloride (500 ml) and saturated sodium hydrogen carbonate (500 ml) in a separatory funnel. The organic phase was removed and the residual aqueous phase was extracted with ethyl acetate (5×300 ml). The combined organic phases were dried over sodium sulfate (500 g) and then vacuum filtered through a glass frit Buchner funnel with a 20 mm layer of Celite. The filter cake was displacement washed with ethyl acetate (250 ml). The clear filtrate was concentrated under reduced pressure to provide a clear pale yellow oil (135 g), as the desired crude product. The material was purified by flash column chromatography eluting with a gradient of 100% hexane to 60% ethyl acetate in hexane over 1 h collecting 450 ml fractions. Note: The product can be detected by TLC analysis on silica gel eluting with 3:1 Hex/EtOAc and visualized under UV. The product fractions were combined and concentrated under reduced pressure to provide a clear colorless oil (132 g, 1.18 mol, 86% yield) as the desired product 3-methylenetetrahydropyran-2-one.

(222) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.18 (q, J=1.9 Hz, 1H), 5.60 (q, J=1.9 Hz, 1H), 4.40-4.26 (m, 2H), 2.61 (ddt, J=7.0, 6.3, 2.0 Hz, 2H), 1.90-1.75 (m, 2H). The proton NMR indicates about 16 wt % residual ethyl acetate. The corrected yield would then be: (100-16=84) 0.84 (132)=110.9 g (72% yield).

(223) Preparation of this compound in a one-pot procedure has been reported; see J. Org. Chem. 2016, 81, 11235-11249. Distillation of this compound has been reported at 52° C. and 0.2 Torr in Synthesis 1985, (1), 35-38.

Step 2: Synthesis of 3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one ((±)-4)

(224) ##STR00310##

(225) A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, a cooling bath used as secondary containment, a J-Kem temperature probe, an addition funnel and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with 2-nitropropane (104.9 g, 1.177 mol). Stirring was commenced and the pot temperature was recorded at 19° C. The vessel was then charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (22.41 g, 147.2 mmol) added neat in one portion, which resulted in a clear light yellow solution. No exotherm was observed. The addition funnel was charged with a solution of 3-methylenetetrahydropyran-2-one (110 g, 981.0 mmol) in acetonitrile (1100 mL), which was added dropwise over 1 h resulting in a clear light yellow solution and a gradual exotherm to 24° C. The reaction mixture continued to stir at room temperature for 3.5 h and then concentrated under reduced pressure. The remaining residue was dissolved in dichloromethane (1000 ml) and partitioned with 500 ml of a 3:2 mixture of 1 M citric acid solution/saturated sodium chloride solution. Note: The resulting organic phase is a clear pale blue solution and the aqueous phase is a slightly cloudy very pale blue solution. The organic phase was removed and the residual aqueous was extracted with dichloromethane (300 ml). The combined organic phases were washed with saturated sodium chloride solution (300 ml), dried over sodium sulfate (250 g) and then filtered through a glass frit Buchner funnel. The filtrate was concentrated under reduced pressure to a volume of about 200 ml. The clear pale blue dichloromethane solution was diluted with methyl tert-butyl ether (1500 ml) and the cloudy solution was concentrated under reduced pressure to a volume of about 200 ml which provided a suspension. The mixture was diluted with methyl tert-butyl ether (1500 ml) and concentrated under reduced pressure to a volume of about 250 ml. The resulting suspension was allowed to stand at ambient temperature overnight (about 12 h). The solid was collected by vacuum filtration in a glass frit Buchner funnel and the filter cake was displacement washed with cold methyl tert-butyl ether (2×150 ml) and then pulled for 30 min. The material was further dried in a vacuum oven at 45° C. for 5 h to provide the desired product 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (160 g, 0.795 mol, 81% yield), as a white solid.

(226) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 4.34 (ddd, J=11.1, 9.3, 4.3 Hz, 1H), 4.20 (dt, J=11.1, 5.1 Hz, 1H), 2.75-2.62 (m, 1H), 2.56 (dd, J=14.9, 5.2 Hz, 1H), 2.01-1.89 (m, 2H), 1.89-1.67 (m, 2H), 1.55 (d, J=6.0 Hz, 6H), 1.44 (dddd, J=12.8, 11.5, 8.1, 6.6 Hz, 1H). ESI-MS m/z calc. 201.10011, found 202.0 [M+1].

(227) Retention time: 0.97 min as an off white solid.

Step 3: Synthesis of 3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one ((f)-3)

(228) ##STR00311##

(229) A solution of 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (122 g, 606.3 mmol) in ethanol (2000 mL) purged with nitrogen then Raney Ni (40 g of 50% w/w, 340 mmol) (washed twice with water and once with ethanol, by mixing and decantation) was added. The mixture was purged with nitrogen then hydrogen. The suspension was stirred vigorously and heated at 60° C. for 20 h under hydrogen (1 atm). The reaction was cooled to room temperature, then purged with nitrogen, filtered over celite and carefully washed with ethanol to prevent the residual catalyst from drying out. The clear colorless filtrate was evaporated and the solid residue (105 g) was suspended in MTBE (˜1.5 L) and concentrated at reflux to a thick suspension (˜200 mL MTBE). The solid was collected by filtration and washed with dry ice-cold MTBE. This solid was dissolved in DCM (˜300 mL) under warming and slowly diluted with MTBE (˜1 L) with seeding to give a colorless suspension. The colorless suspension was concentrated at 45° C. under reduced pressure to −500 mL and the suspension was left stirring at room temperature overnight. The colorless suspension was filtered, washed with dry ice-cold MTBE and dried to give 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (94.1 g, 88%)

(230) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.63 (s, 1H), 4.38 (s, 1H), 3.38 (t, J=6.5 Hz, 2H), 2.37 (qd, J=9.5, 4.4 Hz, 1H), 2.02 (dd, J=12.4, 8.6 Hz, 1H), 1.78-1.63 (m, 1H), 1.50-1.33 (m, 3H), 1.16 (d, J=17.9 Hz, 7H). ESI-MS m/z calc. 171.12593, found 172.0 [M+1]+.

Step 4: Synthesis of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3)

(231) ##STR00312##

(232) 3-(3-Hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (1813 g) was separated using a Chiralpak® AZ column eluted with a isocratic mixture of hexane:ethanol (85:15) at ambient temperature to afford (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (810 g) as a colorless solid after removal of the solvent.

(233) 98.6% enantiomeric excess (Chiralpak® AZ column, 210 nm); The (S)-enantiomer elutes at 13.1 min. The (R)-enantiomer elutes at 22.5 min.

Example 17: Alternative Synthesis of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3)

(234) ##STR00313##

Step 1: Synthesis of ethyl 2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate ((f)-39)

(235) ##STR00314##

(236) A 500-mL jacketed reactor, equipped with a reflux condenser, nitrogen purge, stirrer at 450 rpm, and jacket at 20° C., was loaded with 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (55.0 g, 273.3 mmol, 1.0 equiv) and EtOH (440.0 mL, 8.0 vol), and stirred. The starting material did not dissolve. To the reaction mixture was added HCl, 4M Dioxane (13.67 mL of 4 M, 54.66 mmol, 0.20 equiv) causing a 2° C. temperature increase, followed by endotherm and drop in temperature to 19° C. Starting material did not dissolve. The reaction progress was followed by HPLC and deemed complete after 2 h (>98.0% conversion). The reaction solution was neutralized with aqueous 20% KHCO.sub.3 and the resulting mixture was then partially concentrated to remove bulk EtOH (75-85% of EtOH removed). The mixture was diluted with 2-MeTHF (550.0 mL, 10.0 vol) and water (275.0 mL, 5.0 vol), then transferred back to the 500 mL reactor, stirred, then stopped and layers allowed to separate, and the aqueous layer drained. The organic layer was washed with brine (165.0 mL, 3.0 vol). The organic layer was dried over Na.sub.2SO.sub.4, filtered through celite and cake washed with 2-MeTHF (110.0 mL, 2.0 vol). The clear, light amber filtrate was concentrated to provide the desired product ethyl 2-(3-hydroxypropyl)-4-methyl-4-nitro-pentanoate (62.98 g, 93%) as light amber oil.

(237) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 4.43 (br s, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.35 (t, J=6.3 Hz, 2H), 2.38-2.24 (m, 2H), 2.07-1.96 (m, 1H), 1.50 (m, 7H), 1.46-1.28 (m, 1H), 1.18 (t, J=7.1 Hz, 3H).

Step 2: Synthesis of ethyl (S)-2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate (39)

(238) ##STR00315##

(239) A 500 ml jacketed reactor, equipped with reflux condenser and nitrogen purge, stirrer at 450 rpm, jacket at 35° C. was loaded with pH 7.93 Phosphate buffer, 0.8M (250.0 mL) and ethyl 2-(3-hydroxypropyl)-4-methyl-4-nitro-pentanoate (5 g, 20.22 mmol, 1.0 equiv) and stirred to produce a suspension. Enzyme Lipase from Rhizomucor miehei (125.0 mL, 25.0 vol, Palatase® 20,000 L) was added. The resulting reaction mixture was sampled and had a starting pH of 7.63. Reaction allowed to run at 35° C. The reaction progress was followed by chiral GC, and deemed complete after two days (>99.0% of desired ester remains). Once complete, the reaction was cooled to 20° C. and the product extracted into MTBE (250.0 mL, 50 vol), resulting in a large emulsion in the organic layer, that was separated from the aqueous layer. The aqueous layer was re-extracted with MTBE (125.0 mL, 25.0 vol). The emulsified organic layers were combined and filtered through Celite to break up the emulsion, returned to the rinsed reactor, and the aqueous phase was separated from the organic layer. The organic (product) layer was washed with 20% aq Na.sub.2CO.sub.3 (50.00 mL, 10.0 vol), 20% aq Na.sub.2CO.sub.3 (25.00 mL, 5.0 vol), 20% aq Na.sub.2CO.sub.3 (25.00 mL, 5.0 vol), and lastly with 20% aq Na.sub.2CO.sub.3 (25.00 mL, 5.0 vol). The organic layer was then washed with water (25.00 mL, 5.0 vol), then with 10% brine (25.00 mL, 5.0 vol). The washed organic layer was concentrated in a rotovap (45° C., vacuum) to provide 2.01 g of ethyl (S)-2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate as light amber oil, enriched to 99.7% of desired enantiomer.

Step 3: Synthesis of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3)

(240) ##STR00316##

(241) Ethyl (S)-2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate (5 g, 20.22 mmol) in ethanol (250 mL) was cycled three times with vacuum/nitrogen and Raney Ni (2.374 g of 50% w/w, 20.22 mmol) (washed twice with water and once with ethanol, by mixing and decantation) was added. The mixture was cycled three times vacuum/nitrogen and then three times vacuum/hydrogen. The suspension was stirred vigorously and heated at 60° C. under hydrogen (2 bar) until the reaction was completed.

(242) The reaction was cooled to room temperature, cycled 3 times with vacuum/nitrogen, filtered over Celite and washed with ethanol (50 mL). The solvent was removed from the filtrate then MeCN (50 mL) was added then the solvent was removed to afford (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (2.88 g, 83%) as off-white solid.

(243) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.63 (s, 1H), 4.38 (s, 1H), 3.38 (t, J=6.5 Hz, 2H), 2.37 (qd, J=9.5, 4.4 Hz, 1H), 2.02 (dd, J=12.4, 8.6 Hz, 1H), 1.78-1.63 (m, 1H), 1.50-1.33 (m, 3H), 1.16 (d, J=17.9 Hz, 7H).

(244) ESI-MS m/z calc. 171.12593, found 172.0 [M+1]+.

Example 18: Synthesis of tert-butyl (S)-2,2-dimethyl-4-(3-((6-sulfamoylpyridin-2-yl)amino)propyl)pyrrolidine-1-carboxylate

(245) ##STR00317##

Step 1: Synthesis of (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (2)

(246) ##STR00318##

(247) To a 50 L reactor, stirring at 150 rpm, equipped with a jacket set to 40° C. and reflux condenser (10° C.) with nitrogen purge, was added 2-MeTHF (10.00 L, 10 vol) followed by portion-wise addition of LAH pellets (332.5 g, 8.760 mol, 1.50 equiv). After pellet addition, the internal temperature was recorded at 38° C. The stirrer speed was then adjusted to 175 rpm, and the mixture was heated to 75° C. internal temperature. To a 20 L RBF was added (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (1,000 g, 5.840 mol, 1.00 equiv) and 2-MeTHF (10.00 L, 10 vol). The resulting mixture was stirred and heated in a water bath at 65° C. The resulting mixture was added over the course of 2 h into the reactor containing the LAH mixture via an addition funnel, which was heated. The mixture was stirred and then quenched using the Fieser method. Water was added drop-wise (400.0 mL, 1×LAH wt), at 3.5° C., jacket at −2° C., using reactor temperature control, maintaining internal temperature control <30° C. Sodium hydroxide (aqueous, 15%; 400.0 mL, 1×LAH wt) was added, followed by portion-wise addition of water (400.0 mL, 1×LAH wt). The resulting mixture was heated to 60° C. for at least 30 min, and then cooled to 25±5° C. Celite (200 grams, 20 wt %) was added, stirred, and then packed a 12-inch diameter QVF filter with a half-inch layer of Celite and filtered the mixture from the reactor. The reactor was rinsed with 2-MeTHF (4.0 L, 4.0 vol) and the resulting mixture was filtered. The filtrate (clear, light amber) was concentrated in vacuo (50° C. bath, vacuum) to afford a clear oil (872 grams, 94.95% yield).

Step 2: Synthesis of tert-butyl (S)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (42)

(248) ##STR00319##

(249) To a 50 L glass, jacketed reactor, with the jacket set to 20° C., stirring at 175 rpm, and condenser set at 20° C., with N.sub.2 purge, was added water (3.480 L, 4.0 vol) and potassium carbonate (1.914 kg, 13.85 mol, 2.5 equiv). To the resulting mixture was then added a solution of (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (870 g, 5.532 mol, 1.0 equiv) in 2-MeTHF (3.480 L, 4.0 vol). 2-MeTHF (3.480 L, 4.0 vol) and Boc.sub.2O (1.096 kg, 5.023 mol, 0.90 equiv) were combined in a glass container. The reactor temperature was set to maintain 20° C. before addition of mixture of 2-MeTHF and Boc.sub.2O via addition funnel over the course of 35 min. The resulting mixture was stirred for 30 min.

(250) To the resulting emulsion was added L-glutamic acid (203.5 g, 1.383 mol, 0.25 equiv) and the emulsion was stirred overnight at room temp. The stirrer was stopped and layers allowed to separate. Water (2.610 L, 3.0 vol) was added, and the mixture stirred. The organic layer was isolated, and the aqueous layer was extracted with 2-MeTHF (2.610 L, 3.0 vol). The combined organic layers were washed with aqueous sodium bisulfate (0.5 M, 1.740 L, 2.0 vol), aq layer pH acidic, then washed with aq 0.5M NaHSO.sub.4 (870.0 mL, 1.0 vol). The organic layer was then washed with Aq 0.5M K.sub.2CO.sub.3 (1.740 L, 2.0 vol) (pH 12 with pH strip), and aq 0.5M K.sub.2CO.sub.3 (1.740 L, 2.0 vol). The organic layer was then washed with brine (870.0 mL, 1.0 vol), then dried over Na.sub.2SO.sub.4, and filtered through Celite. The filter cake was rinsed with 2-MeTHF (870.0 mL, 1.0 vol). The filtrate was concentrated in vacuo to afford tert-butyl (S)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1,336 g, 94%) as a clear, viscous oil.

Step 3: Synthesis of tert-butyl (S)-2,2-dimethyl-4-(3-(((4-nitrophenyl)sulfonyl)oxy)propyl)pyrrolidine-1-carboxylate

(251) ##STR00320##

(252) To a 50 L jacketed reactor, with jacket set to 20° C., stirring at 175 rpm, a reflux condenser (10° C.), and a nitrogen purge was added tert-butyl (S)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1,330 g, 5.168 mol, 1.0 equiv), DCM (7.980 L, 6.0 vol) and 4-nitrobenzenesulfonyl chloride (1.753 kg, 7.752 mol, 1.50 equiv). The resulting mixture was stirred with a reactor internal temperature of 5° C. Triethylamine (1.046 kg, 10.34 mol, 2.0 equiv) was added via addition funnel at a rate to maintain a reaction temperature of less than 15° C.

(253) The resulting mixture was stirred for approximately 30 min before water (3.990 L, 3.0 vol) and saturated aqueous sodium bicarbonate (2.660 L, 2.0 vol) were added. The resulting mixture was stirred and warmed to room temperature. Addition exotherm went from 5° C. to 12° C. at this scale, jacket then set to 20° C. Stirring was then stopped, the organic was isolated and washed with saturated aqueous sodium bicarbonate (3.990 L, 3.0 vol). The amber organic solution was dried over sodium sulfate, and filtered through Celite. The filter cake was washed with DCM (1.330 L, 1.0 vol). The filtrate was partially concentrated in vacuo, and then IPA (5.320 L, 4.0 vol) was added. Partially concentrated in vacuo and added seed material (tert-butyl (S)-2,2-dimethyl-4-(3-(((4-nitrophenyl)sulfonyl)oxy)propyl)pyrrolidine-1-carboxylate, 250 mg), returned flask to rotovap, stirred at room temp overnight, then added ice-water bath, continued stirring, cooling for 1-2 h. The mixture was filtered through a QVF filter (12-inch diameter). The filter cake was washed with cold IPA (1.330 L, 1.0 vol), and the filter cake was scooped into a rotovap flask and dried in vacuo (50° C., rotovap, vacuum). The solid was dried to 2,091 grams (91.43% yield) as beige colored fine solid.

Step 4: Synthesis of tert-butyl (S)-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (44)

(254) ##STR00321##

(255) Step 4a: To a 50 L jacketed reactor with a jacket set to 20° C., stirring at 175 rpm, and a reflux condenser (10° C.) with nitrogen purge was added tert-butyl (S)-2,2-dimethyl-4-(3-(((4-nitrophenyl)sulfonyl)oxy)propyl)pyrrolidine-1-carboxylate (2090 g, 4.723 mol, 1.00 equiv) and NMP (10.45 L, 5.0 vol). The system was set to maintain an internal temperature of 20° C. while stirring. Sodium azide (307.0 g, 4.723 mol, 1.00 equiv) was added in two portions into the reactor and rinsed in with NMP (2.090 L, 1.0 vol). The resulting mixture was stirred for 1 h before diluting with 2-MeTHF (25.08 L). The organic layer was isolated, washed with 1:1 water, saturated NaHCO.sub.3solution (16.72 L, 8.0 vol). Additional water was added (4.180 L, 2.0 vol), stirred, and then allowed to separate. The aqueous layer was extracted with 2-MeTHF (6.270 L, 3.0 vol). The organic layers were combined and washed with 2:1 water/sodium bicarbonate (6.270 L, 3.0 vol total, 2 vol water:1 vol bicarb), and then washed with 2:1 water/brine (6.270 L, 3.0 vol), 1:1 water/brine (4.180 L, 2.0 vol), and with brine (4.180 L, 2.0 vol). The organic layer was dried over sodium sulfate then filtered through Celite. The filter cake was washed with 2-MeTHF (2.090 L, 1.0 vol), and the filtrate was partially concentrated in the rotovap to 5+/−1 volumes. Concentrated to 3.02 kg as clear amber solution. Estimate 75% yield that was used without further purification.

(256) Step 4b: To a Buchi 1 L pressure system with a jacket at 20° C., purging with nitrogen was added tert-butyl (4S)-4-(3-azidopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (200 g, 708.3 mmol) solution in 2-MeTHF (˜700 mL), followed by addition of platinum oxide (2.0 g, 8.85 mmol, 1.0 wt %), and rinsed in with 2-MeTHF (50.00 mL, 0.25 vol). The resulting mixture was stirred at 400 rpm and the reaction chamber was degassed with three cycles of N.sub.2/vacuum, followed with three cycles of H.sub.2/vacuum. The H.sub.2 pressure was set to 2.0 bar and system set for automatic H.sub.2 feed, maintaining 2.0 bar, stirring increased to 900 rpm at 21.1° C. Then, with the jacket set to 20° C., the headspace was evacuated by cycling nitrogen/vacuum times. The reaction mixture was filtered through Celite. The filter cake was rinsed with 2-MeTHF (100.0 mL, 0.5 vol), and the filtrate transferred to a stirred vessel and diluted with 2-MeTHF (2000.0 mL, 10.0 vol), followed by addition of cold aqueous 1N HCl (1.062 L of 1 M, 1.062 mol, 5.0 vol) while stirring. The stirring was stopped, the pH was measured with indicating strips, and the layers separated. The organic layer was extracted with cold aqueous 1 N HCl (354.1 mL of 1 M, 354.2 mmol, 0.5 equiv). The aqueous layers were combined in the reactor and stirred at room temp. 2-MeTHF (1.600 L, 8.0 vol) was added and the mixture was basified by adding aqueous (4 M) NaOH (approximately 354.2 mL of 4 M, 1.417 mol) as needed. The layers were separated, then drained into clean container. The aqueous layer was isolated and extracted with 2-MeTHF (400.0 mL, 2.0 vol). The organic layers were combined and added to the reactor, then washed with brine (600.0 mL, 3.0 vol) then dried over sodium sulfate then filtered through celite. The filter cake was rinsed with 2-MeTHF (400.0 mL, 2.0 vol). The filtrate was concentrated in vacuo (50° C., vacuum) to afford an oil. The material was used without further purification.

(257) Step 4c: The crude amine oil (990 grams, 3.87 mol) was diluted with 2-MeTHF (25.0 L, 25 vol) transferred into a 50 L reactor, and stirred at 25° C. Measured the required amount of oxalic acid (208.9 grams, 425.0 mmol, 0.60 equiv) and dispensed into a glass carboy, then added 2-MeTHF (5.0 L, 5.0 vol) and stirred to dissolve the acid. Began slow addition of the oxalic acid solution to the amine solution. Note that salts start forming on addition and may require slow addition to prevent large chunks of solid from forming. Salts appeared to form a gel that slowly changed. The mixture was stirred at room temp overnight. Appearance of the solid changed from a gel to a mixture containing fine solids. The mixture was filtered (slow filtration), cake then washed with 2-MeTHF (4.00 L, 4.0 vol) and pulled dry in the filter. The cake was scooped out of the filter and dried in vacuo (50° C., vacuum, rotovap). Obtained 1,057 grams of tert-butyl (S)-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate hemi-oxalate salt, as an off-white solid. The crude amine oil (990 grams, 3.87 mol) was diluted with 2-MeTHF (25.0 L, 25 vol) transferred into a 50 L reactor, and stirred at 25° C. Oxalic acid (208.9 grams, 425.0 mmol, 0.60 equiv) was measured and dispensed into a glass carboy, then dissolved in 2-MeTHF (5.0 L, 5.0 vol) with stirring to dissolve the acid. Slow addition of the oxalic acid solution to the amine solution was carried out. Note that salts start forming on addition and may require slow addition to prevent large chunks of solid from forming. Salts appeared to form a gel that slowly changed. The mixture was stirred at room temp overnight. The appearance of the solid changed from a gel to a mixture containing fine solids. The mixture was filtered (slow filtration), cake then washed with 2-MeTHF (4.00 L, 4.0 vol) and pulled dry in the filter. The cake was scooped out of the filter and dried in vacuo (50° C., vacuum, rotovap). Obtained 1,057 grams of tert-butyl (S)-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate hemi-oxalate salt as an off-white solid.

Example 19: Synthesis of 2-chloro-6-(3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinic acid

(258) ##STR00322##

Step 1: Synthesis of ethyl 2-chloro-6-(3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate

(259) ##STR00323##

(260) A suspension of 3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazole (40.0 g, 196 mmol), ethyl 2,6-dichloronicotinate (43.1 g, 196 mmol), and K.sub.2CO.sub.3 (35.2 g, 255 mmol) in DMF (240 mL) was stirred at RT. Dissolution resulted in an endotherm from 22 to 16° C. In one portion, DABCO (3.3 g, 29 mmol) was added. The addition was mildly exothermic and raised the reaction temperature from 17 to 23° C. over 20 min. The reaction temperature was maintained at 20-30° C. After ˜20 h, HPLC analysis showed the reaction was completed (no ethyl 2,6-dichloronicotinate remained; 90% AUC). The mixture was diluted with drop-wise addition of water (400 mL)-white solid formed and the temperature gradually rose from 22 to 32° C. The mixture was re-cooled to maintain the temperature at 15-25° C. After an unsuccessful filtration (solid blinded the filter) the suspension was diluted with EtOAc (480 mL) and the phases were separated. The organic phase was washed with water (200 mL)/brine (50 mL) (2×); the organic phase was dried (Na.sub.2SO.sub.4) and concentrated (40° C./30 torr) to afford crude ethyl 2-chloro-6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate (73.1 g; 96%) as an amber oil which became crystalline.

(261) The crude solid was dissolved in warm (80° C.) i-PrOH (200 mL) and allowed to cool to RT over 2 h. The solution was seeded at 38-40° C. for a slow nucleation/crystallization event. At 35-34° C. much crystallization was observed. The suspension was allowed to stir at RT overnight.

(262) The resultant suspension was very thick (oatmeal consistency). The solid was collected by filtration (sintered-glass/paper); the filter-cake was washed with i-PrOH (50 mL), air-dried with suction and then vacuum-dried (55° C./300 torr/N.sub.2 bleed) to afford ethyl 2-chloro-6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate (60.2 g; 79%; 98.6% AUC) as a white powder. The filtrate was cooled to 3° C. and a 2.sup.nd crop was collected (5.8 g; 8%) as a white powder of acceptable purity (98% AUC). Total Yield: 60.2+5.8=66.0 g (87%).

(263) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.45-8.36 (m, 2H), 7.73 (d, J=8.3 Hz, 1H), 6.19 (d, J=2.8 Hz, 1H), 4.34 (q, J=7.1 Hz, 2H), 4.25 (t, J=6.7 Hz, 2H), 1.82 (q, J=6.7 Hz, 2H), 1.47 (t, J=6.6 Hz, 1H), 1.34 (t, J=7.1 Hz, 4H), 0.89-0.77 (m, 1H), 0.83 (s, 4H), 0.71-0.60 (m, 3H), 0.54-0.44 (m, 2H).

Step 2: Synthesis of 2-chloro-6-(3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinic acid

(264) ##STR00324##

(265) A solution of ethyl 2-chloro-6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate (62.0 g, 160 mmol) in THF (248 mL) and EtOH (186 mL) was stirred at ambient temperature (13° C.). A 2 M aqueous solution of NaOH (approximately 96 mL; 192 mmol) was added in one portion; an exotherm from 13 to 20° C. was observed. After 1 h, UPLC-MS analysis showed reaction completion. The reaction solution was concentrated (40° C./50 torr) to remove most of the organic solvent. The concentrate was diluted with water (248 mL) and 2-MeTHF (750 mL) and then 2 M HCl (100 mL, 200 mmol) was added while maintaining the internal temperature below 20° C. The phases were separated and the organic phase was washed with water (2×200-mL); dried (Na.sub.2SO.sub.4), and concentrated to afford crude 2-chloro-6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinic acid (62.4 g (109% of theory) as a white powder. The product contains some residual solvent(s).

(266) The crude product was recrystallized from warm (106° C.) PhMe (5 VolEq), seeded at −95° C. and cooled to RT over 2 h and then further to 10° C. The solid was collected by filtration, washed with cold PhMe (1 VolEq), and the filter-cake was dried with suction and then in a vacuum oven (40° C./100 torr) to afford 2-chloro-6-(3-(2-(dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinic acid (88% yield) as a white powder.

(267) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.61 (s, 1H), 8.44-8.36 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 6.17 (d, J=2.9 Hz, 1H), 4.24 (t, J=6.7 Hz, 2H), 1.82 (q, J=6.7 Hz, 2H), 1.47 (t, J=6.5 Hz, 1H), 0.89-0.77 (m, 2H), 0.83 (s, 2H), 0.71-0.60 (m, 2H), 0.50 (ddd, J=8.2, 4.5, 2.2 Hz, 2H).

Example 20: Synthesis of (14R)-8-[3-(2-{dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl}ethoxy)-H-pyrazol-1-yl]-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione

(268) ##STR00325##

Step 1: Synthesis of tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)propyl)-2,2-dimethylpyrrolidine-1-carboxylate

(269) ##STR00326##

(270) A biphasic mixture of tert-butyl (4R)-4-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (22.0 g, 85.8 mmol) in PhMe (132 mL) and NaOH (86 mL of 2 M, 172 mmol) was cooled at 0-10° C., then a solution of Cbz-Cl (22.0 g, 18.4 mL, 129 mmol) in PhMe (44 mL) was added over 15 min while maintaining the reaction temperature below 10° C. Once the reaction was complete, the biphasic mixture was warmed to room temperature and the phases were separated. The aqueous phase was extracted with PhMe (44.00 mL) then the combined organic phases were washed with water (88 mL), dried (Na.sub.2SO.sub.4), and concentrated to afford tert-butyl (4R)-4-[3-(benzyloxycarbonylamino)propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (36.1 g; 108%) as a colorless oil.

Step 2: Synthesis of benzyl (R)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate

(271) ##STR00327##

(272) A solution of tert-butyl (4R)-4-[3-(benzyloxycarbonylamino)propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (30.0 g, 76.8 mmol) in DCM (60 mL) was treated with HCl (96 mL of 4 M, 384 mmol) in dioxane and stirred at room temperature until the reaction was complete, then the solvents were removed under vacuum. The concentrate was partitioned between water (180 mL) and MTBE (120 mL) and the phases were separated. The aqueous phase was washed with MTBE (120 mL). The aqueous phase was diluted with MTBE (180 mL) and basified with NaOH (46 mL of 2 M, 92 mmol) (pH ˜14). The phases were separated and the aqueous phase was extracted with MTBE (120 mL). The combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated (40° C./20 torr) to afford benzyl N-[3-[(3R)-5,5-dimethylpyrrolidin-3-yl]propyl]carbamate (15.2 g, 68%) as a colorless liquid.

(273) UPLC-MS analysis: tR=0.99 min/M+1=291 (conforms to structure).

(274) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.43-7.23 (m, 5H), 5.09 (s, 2H), 4.79 (s, 1H), 3.26-3.05 (m, 3H), 2.55 (dd, J=11.0, 8.0 Hz, 1H), 2.13 (dq, J=15.5, 7.8 Hz, 1H), 1.79 (dd, J=12.5, 8.0 Hz, 2H), 1.48 (q, J=7.3 Hz, 2H), 1.37 (ddd, J=9.8, 7.2, 3.3 Hz, 2H), 1.18 (s, 3H), 1.12 (s, 4H).

Step 3: Synthesis of 2-chloro-6-(3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinic acid

(275) ##STR00328##

(276) To a solution of tert-butyl 2-chloro-6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylate (10.0 g, 24.0 mmol) in DCM (100 mL) was added trifluoroacetic acid (26 mL, 338 mmol). The reaction stirred under nitrogen gas at room temperature for 16 h. The reaction mixture was concentrated to afford a white solid. To the white solid was added MTBE and the mixture was concentrated three times to give 2-chloro-6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (9.00 g, 96%). The crude NMR showed MTBE and some baseline impurities.

(277) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.61 (s, 1H), 8.50-8.32 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 6.17 (d, J=2.9 Hz, 1H), 4.24 (t, J=6.7 Hz, 2H), 1.82 (q, J=6.7 Hz, 2H), 1.47 (t, J=6.5 Hz, 1H), 0.88-0.78 (m, 4H), 0.68-0.61 (m, 2H), 0.50 (ddd, J=8.2, 4.5, 2.2 Hz, 2H).

Step 4: Synthesis of 2-chloro-6-(3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-H-pyrazol-1-yl)nicotinamide

(278) ##STR00329##

(279) A suspension of 2-chloro-6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (7.5 g, 20.8 mmol) in 2-MeTHF (45 mL) and DMF (152 mg, 161 μL, 2.1 mmol) was stirred at room temperature then SOCl.sub.2 (3.35 g, 2.05 mL, 28.1 mmol) was added and heated at 40° C. Once the reaction was completed, the reaction was added to a separate flask containing a cooled solution of NH.sub.4OH (approximately 28 mL of 14.8 M, 417 mmol) in water (26 mL) while maintaining the internal temperature below 15° C. Once the reaction was completed (20 min) the mixture was diluted with MTBE (120 mL) and water (60 mL) then EtOAc (180 mL). The phases were separated then the organic phase was dried (Na.sub.2SO.sub.4) and concentrated to afford a beige powder. The powder was stirred with MTBE (50 mL; 7 VolEq) and warmed to form a slurry then cooled to room temperature. The solid was collected by filtration then rinsed with MTBE (2×5-mL) and dried to afford 2-chloro-6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxamide (6.70 g; 90%) as an off-white powder.

(280) HPLC analysis: 98.6% AUC (272 nm)

(281) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.38 (d, J=2.8 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 6.13 (d, J=3.0 Hz, 1H), 4.24 (t, J=6.7 Hz, 2H), 1.82 (q, J=6.7 Hz, 2H), 1.47 (t, J=6.5 Hz, 1H), 0.90-0.76 (m, 4H), 0.69-0.58 (m, 2H), 0.56-0.45 (m, 2H).

Step 5: Synthesis of benzyl (R)-(3-(1-(3-carbamoyl-6-(3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate

(282) ##STR00330##

(283) A suspension of 2-chloro-6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxamide (5.0 g, 13.9 mmol), benzyl N-[3-[(3R)-5,5-dimethylpyrrolidin-3-yl]propyl]carbamate (4.86 g, 16.7 mmol), K.sub.2CO.sub.3 (approximately 5.8 g, 42 mmol), and ZnCl.sub.2 (approximately 1.9 g, 14 mmol) in n-BuOAc (40 mL) was heated at 120° C. until the reaction was complete (˜2.5 days).

(284) The suspension was diluted with EtOAc (60 mL) and acidified with HCl (approximately 42 mL of 2 M, 84 mmol); C.sub.02 degassing; pH ˜1. The phases were separated and the aqueous phase was extracted with EtOAc (60 mL); combined organic phases and washed with water (60 mL), dried (Na.sub.2SO4), and concentrated to afford 14.0 g (164%) of a dark amber liquid (residual n-BuOAc remained).

(285) Diluted with DCM and purified by flash column chromatography eluting with EtOAc/hexanes. The fractions containing the desired product were combined and concentrated to afford benzyl N-[3-[(3R)-1-[3-carbamoyl-6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]-2-pyridyl]-5,5-dimethyl-pyrrolidin-3-yl]propyl]carbamate (3.05 g; 36%) as a yellow foam.

(286) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.19 (d, J=2.7 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.42-7.20 (m, 7H), 6.84 (d, J=8.0 Hz, 1H), 6.05 (d, J=2.7 Hz, 1H), 5.01 (s, 2H), 4.20 (t, J=6.7 Hz, 2H), 3.32 (t, J=10.4 Hz, 1H), 3.19 (t, J=8.8 Hz, 1H), 3.01 (q, J=6.5 Hz, 2H), 2.21 (s, 1H), 1.94 (dd, J=11.9, 5.6 Hz, 1H), 1.81 (q, J=6.6 Hz, 2H), 1.61 (s, 3H), 1.57 (s, 3H), 1.53-1.23 (m, 6H), 0.90-0.77 (m, 4H), 0.67-0.60 (m, 2H), 0.53-0.46 (m, 2H).

Step 6: Synthesis of benzyl (R)-(3-(1-(6-(3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate

(287) ##STR00331##

(288) A solution of benzyl N-[3-[(3R)-1-[3-carbamoyl-6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]-2-pyridyl]-5,5-dimethyl-pyrrolidin-3-yl]propyl]carbamate (2.50 g, 4.08 mmol) in 2-MeTHF (15 mL) was cooled at 0-5° C. then a solution of 6-fluoropyridine-2-sulfonyl chloride (approximately 1.19 g, 6.12 mmol) in 2-MeTHF (5 mL) was added, followed by lithium 2-methylbutan-2-olate (3.3 mL of 40% w/w, 10.2 mmol) over 15 min while maintaining the reaction temperature below 5° C. Analysis showed 10-15% of unreacted starting material, so an additional portion of 6-fluoropyridine-2-sulfonyl chloride (0.20 g, 1.0 mmol), followed by lithium 2-methylbutan-2-olate (330 μL of 40% w/w, 1.0 mmol), were added. The mixture was stirred until the reaction was complete (˜20 min) then partitioned between EtOAc (20 mL) and HCl (12 mL of 1 M, 12 mmol). The phases were separated and the organic phase was washed with water (10 mL), then dried (Na.sub.2SO.sub.4) and concentrated to afford a brown taffy/foam. Purification by normal phase column chromatography (gradient EtOAc/hexanes) followed by reversed-phase column chromatography (gradient CH.sub.3CN/H.sub.2O) afforded benzyl N-[3-[(3R)-1-[6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]-3-[(6-fluoro-2-pyridyl)sulfonylcarbamoyl]-2-pyridyl]-5,5-dimethyl-pyrrolidin-3-yl]propyl]carbamate (1.10 g; 35%; 97+% AUC) as a white powder.

(289) A less pure fraction (0.80 g; 84% AUC) was dissolved in warm EtOH (˜10 mL), stirred, and allowed to cool to RT. After ˜10 min crystallization occurred. The suspension was stirred for ˜1 h and the solids were collected by filtration (fritted syringe). The filter-cake was rinsed with EtOH (3 mL) and the solid air-dried/vacuum dried (55° C.) to afford additional benzyl N-[3-[(3R)-1-[6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]-3-[(6-fluoro-2-pyridyl)sulfonylcarbamoyl]-2-pyridyl]-5,5-dimethyl-pyrrolidin-3-yl]propyl]carbamate (0.61 g; 76% recovery) of a free-flowing, white powder.

(290) HPLC analysis: 95.2% AUC (272 nm).

(291) Total yield=1.10 g+0.61 g=1.71 g (54%).

(292) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.34 (q, J=7.8 Hz, 1H), 8.13 (dd, J=7.4, 2.0 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.59 (dd, J=8.3, 2.3 Hz, 1H), 7.37 (d, J=4.2 Hz, 4H), 7.34-7.21 (m, 2H), 6.94 (d, J=8.3 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 5.05 (s, 2H), 4.22 (t, J=6.7 Hz, 2H), 3.01 (hept, J=6.7 Hz, 2H), 2.46 (dd, J=10.4, 7.0 Hz, 1H), 2.13 (s, 1H), 1.89 (dd, J=11.8, 5.5 Hz, 1H), 1.81 (q, J=6.6 Hz, 2H), 1.54 (s, 6H), 1.47 (t, J=6.5 Hz, 1H), 1.34 (td, J=13.1, 12.6, 6.7 Hz, 3H), 1.17 (dt, J=16.1, 5.2 Hz, 1H), 0.97 (dt, J=13.4, 8.8 Hz, 1H), 0.89-0.75 (m, 4H), 0.71-0.57 (m, 2H), 0.56-0.41 (m, 2H).

(293) .sup.19FNMR (376 MHz, DMSO) δ −65.73.

Step 7: Synthesis of (R)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide ((R)-53)

(294) ##STR00332##

(295) A mixture of benzyl N-[3-[(3R)-1-[6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]-3-[(6-fluoro-2-pyridyl)sulfonylcarbamoyl]-2-pyridyl]-5,5-dimethyl-pyrrolidin-3-yl]propyl]carbamate (1.00 g, 1.30 mmol) and Pd on carbon (69 mg of 10% w/w) in MeOH (8 mL) was stirred under an atmosphere of H.sub.2 (1 bar) at ˜40° C. until the reaction was completed (2.5 h). The catalyst was removed the catalyst by filtration and the filtrate was concentrated to afford crude as a white taffy/solid. Purification by reversed-phase flash column (gradient CH.sub.3CN/H.sub.2O) followed by slurrying in MTBE (10 mL) afforded 2-[(4R)-4-(3-aminopropyl)-2,2-dimethyl-pyrrolidin-1-yl]-6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]-N-[(6-fluoro-2-pyridyl)sulfonyl]pyridine-3-carboxamide (190 mg; 23%; 95.0% AUC) as a white powder.

(296) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.15 (d, J=2.7 Hz, 1H), 8.11 (q, J=7.9 Hz, 1H), 7.86 (dd, J=7.4, 2.2 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.24 (dd, J=8.3, 2.4 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.01 (d, J=2.7 Hz, 1H), 4.20 (t, J=6.7 Hz, 2H), 3.15 (t, J=10.6 Hz, 1H), 3.06 (dd, J=10.9, 7.3 Hz, 1H), 2.82 (hept, J=7.2, 6.3 Hz, 2H), 2.08 (s, 1H), 1.81 (q, J=6.5 Hz, 2H), 1.55 (s, 5H), 1.51 (s, 3H), 1.47 (t, J=6.5 Hz, 1H), 1.42-1.27 (m, 3H), 1.26-1.15 (m, 1H), 0.83 (d, J=5.5 Hz, 4H), 0.64 (dd, J=8.5, 4.2 Hz, 2H), 0.50 (dd, J=8.5, 4.0 Hz, 2H).

Step 8: Synthesis of (14R)-8-[3-(2-{dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ.SUP.6.-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.SUP.11.,.SUP.14..0.SUP.5.,.SUP.10.]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione

(297) ##STR00333##

(298) A suspension of 2-[(4R)-4-(3-aminopropyl)-2,2-dimethyl-pyrrolidin-1-yl]-6-[3-(2-dispiro[2.0.2.sup.4.1.sup.3]heptan-7-ylethoxy)pyrazol-1-yl]-N-[(6-fluoro-2-pyridyl)sulfonyl]pyridine-3-carboxamide (300 mg, 0.4704 mmol), K.sub.2CO.sub.3 (162.5 mg, 1.176 mmol), and MgCl.sub.2 (44.79 mg, 0.4704 mmol) in DMSO (2.400 mL) was heated at 80° C. for ˜6 h until the starting material was consumed. The suspension was partitioned between EtOAc (12 mL) and 0.5 M HCl (4.7 mL, 2.35 mmol). The phases were separated and the aqueous phase extracted with EtOAc (6 mL). The combined organic phases were washed with water (3×2-mL), dried (Na.sub.2SO.sub.4), and concentrated to afford (14R)-8-[3-(2-{dispiro[2.0.2.sup.4.1.sup.3]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ.sup.6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1.sup.11,.sup.14.0.sup.5,.sup.10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (262 mg; 90%) as an amber solid.

(299) HPLC analysis showed 94.8% AUC with a trace (0.2%) of unreacted starting material.

(300) UPLC-MS analysis: M+1=618 (conforms to structure).

(301) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.52 (s, 1H), 8.21 (d, J=2.9 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.12-6.83 (m, 3H), 6.72 (d, J=8.5 Hz, 1H), 6.09 (d, J=2.8 Hz, 1H), 4.22 (td, J=6.8, 2.3 Hz, 2H), 4.04-3.84 (m, 1H), 3.16 (s, 1H), 2.96 (d, J=13.1 Hz, 1H), 2.70 (d, J=11.3 Hz, 1H), 2.13 (s, 1H), 1.84 (dq, J=20.2, 6.6, 5.9 Hz, 4H), 1.70-1.40 (m, 10H), 1.32 (q, J=12.2 Hz, 1H), 0.90-0.75 (m, 4H), 0.65 (dd, J=8.6, 4.2 Hz, 2H), 0.51 (dd, J=8.5, 4.2 Hz, 2H).

Example 21: Synthesis of tert-butyl (S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate

(302) ##STR00334##

(303) A method for preparing tert-butyl (S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 22: Synthesis of (S)-6-bromo-2-(4-(3-(bis-Boc-amino)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide

(304) ##STR00335##

(305) A method for preparing (S)-6-bromo-2-(4-(3-(bis-Boc-amino)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 23: Synthesis of benzyl (S)-(3-(1-(6-bromo-3-carbamoylpyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (45)

(306) ##STR00336##

(307) An alternative method for preparing compound 45 is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 24: Synthesis of (13S)-26-chloro-15,15-dimethyl-5-thia-4,7-diaza-2(2,3),6(2,6)-dipyridina-1(1,3)-pyrrolidinacyclodecaphan-3-one 5,5-dioxide (41)

(308) ##STR00337##

(309) A method for preparing compound 41 is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 25: Synthesis of (R)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-chloro-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide

(310) ##STR00338##

(311) A method for preparing (R)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-chloro-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 26: Diester enzymatic resolution of diethyl 2-(2-methyl-2-nitropropyl)pentanedioate

(312) ##STR00339##

(313) A method for the chiral resolution of diethyl 2-(2-methyl-2-nitropropyl)pentanedioate is shown in the above scheme. In some embodiments, O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 27: Dinitrile enzymatic resolution of 2-(2-methyl-2-nitropropyl)pentanedinitrile

(314) ##STR00340##

(315) A method for the chiral resolution of 2-(2-methyl-2-nitropropyl)pentanedinitrile is shown in the above scheme.

Example 28: Ester Enzymatic Resolution of Ethyl 2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoate (35)

(316) ##STR00341##

(317) A method for the chiral resolution of compound 35 is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 29: Ester enzymatic resolution of ethyl 2-(3-(1,3-dioxoisoindolin-2-yl)propyl)-4-methyl-4-nitropentanoate

(318) ##STR00342##

(319) A method for the chiral resolution of ethyl 2-(3-(1,3-dioxoisoindolin-2-yl)propyl)-4-methyl-4-nitropentanoate shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 30: Enantioselective ring opening of ethyl 4-cyano-6,6-dimethyl-2-oxotetrahydro-2H-pyran-3-carboxylate

(320) ##STR00343##

(321) A method for the chiral resolution of ethyl 4-cyano-6,6-dimethyl-2-oxotetrahydro-2H-pyran-3-carboxylate is shown in the above scheme. In some embodiments, O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 31: Synthesis of 3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol ((f)-42)

(322) ##STR00344##

(323) A method for the chiral resolution of diethyl 2-(2-methyl-2-nitropropyl)pentanedioate is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 32: Synthesis of 2-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)isoindoline-1,3-dione

(324) ##STR00345##

(325) A method for the chiral resolution of 2-(2-methyl-2-nitropropyl)pentanedinitrile is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 33: Synthesis of tert-butyl (3-(5,5-dimethyl-2-oxopyrrolidin-3-ylidene)propyl)carbamate

(326) ##STR00346## ##STR00347##

(327) A method for preparing tert-butyl (3-(5,5-dimethyl-2-oxopyrrolidin-3-ylidene)propyl)carbamate is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 34: Synthesis of tert-butyl (S)-(3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)propyl)carbamate

(328) ##STR00348##

(329) A method for preparing tert-butyl (S)-(3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)propyl)carbamate is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 35: Synthesis of tert-butyl (S)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (31)

(330) ##STR00349##

(331) A method for preparing compound 31 is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 36: Synthesis of tert-butyl (3-(5,5-dimethyl-2-oxopyrrolidin-3-ylidene)propyl)carbamate

(332) ##STR00350##

(333) A method for preparing tert-butyl (3-(5,5-dimethyl-2-oxopyrrolidin-3-ylidene)propyl)carbamate is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 37: Synthesis of 3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)propyl benzoate

(334) ##STR00351##

(335) A method for preparing 3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)propyl benzoate is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 38: Synthesis of tert-butyl 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate

(336) ##STR00352##

(337) A method for preparing tert-butyl 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 39: Synthesis of 1-benzyl-3-(3-(benzyloxy)propyl)-5,5-dimethyl-1,5-dihydro-2H-pyrrol-2-one

(338) ##STR00353##

(339) A method for preparing 1-benzyl-3-(3-(benzyloxy)propyl)-5,5-dimethyl-1,5-dihydro-2H-pyrrol-2-one is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 40: Synthesis of Pyrroline

(340) ##STR00354##

(341) A method for preparing the pyrroline is shown in the above scheme. In some embodiments, N and O may have one or more protecting groups selected from a range of protecting groups disclosed herein.

Example 41: Synthesis of 7,7-dibromodispiro[2.0.2.SUP.4..1.SUP.3.]heptane (54)

(342) ##STR00355##

(343) Compound 18 was prepared by reacting compound 19 with Ti(Oi-Pr).sub.4 and EtMgBr in the presence of MTBE at 20° C. to 25° C. for 14 h. Compound 17 was prepared by reacting compound 18 with PPh.sub.3, Br.sub.2, and pyridine in the presence of DCM at −30° C. to 15° C. for 14 h, then distilling the reaction mixture. Compound 16 was prepared by reacting compound 17 with KOt-Bu in the presence of DMSO at 20° C. to 25° C. for 16 h. Compound 54 was prepared by reacting compound 16 with KOt-Bu and CHBr.sub.3 in the presence of heptane at 0° C. to rt for 17-72 h.

Example 42: Alternative Synthesis of 2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethan-1-ol (8)

(344) ##STR00356##

(345) Compound 55 was prepared by reacting compound 54 with vinylmagnesium bromide and copper(I) iodide in the presence of THF at −40° C. to −10° C. for 4 h. Compound 55 was then reacted with borane-THF, hydrogen peroxide, and sodium hydroxide at 0° C. to provide compound 8.

Example 43: Alternative Synthesis of 2-(dispiro[2.0.2.SUP.4..1.SUP.3.]heptan-7-yl)ethan-1-ol (8)

(346) ##STR00357##

(347) Compound 56 can be prepared by first reacting compound 54 with tert-butylmagnesium chloride and iron(III) acetylacetonate at −10° C. Compound 56 can then be treated in a first step with magnesium metal and iodine in the presence of THF at 50° C., and in a second step with ethylene oxide and Li.sub.2CuCl in the presence of THF at −20° C., to provide compound 8.

OTHER EMBODIMENTS

(348) All publications and patents referred to in this disclosure are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Should the meaning of the terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meaning of the terms defined in this disclosure is intended to be controlling.

(349) The foregoing discussion discloses and describes exemplary embodiments of this disclosure. One skilled in the art will readily recognize, from such discussion and from the accompanying claims, that various changes, modifications, and variations can be made therein without departing from the spirit and scope of this disclosure as defined in the following claims.